Aza (Indole)-, Benzothiophene-, And Benzofuran-3-Sulfonamides

ABSTRACT

Disclosed are sulfonamide compounds with GPR17 modulating properties, which are useful for treating or preventing a variety of CNS and other diseases, in particular for preventing and treating myelinating diseases or disorders.

BACKGROUND

G-protein coupled receptors (GPCRs) constitute the largest family ofmembrane receptors in the cell. They transduce extracellular signals tointracellular effector systems and are involved in a large variety ofphysiological phenomena, therefore representing the most common targetsof pharmaceutical drugs although only a small percentage of GPCRs aretargeted by current therapies.

GPCRs respond to a wide range of ligands. Due to the progress in humangenome sequencing, for about 25% out of the more than 400 GPCRs (notincluding the olfactory

GPCRs) that have been identified, a defined physiologically relevantligand is still lacking. These receptors are known as “orphan GPCRs”.“Deorphanization” and identification of their in vivo roles is expectedto clarify novel regulatory mechanisms and, therefore, to disclose noveldrug targets. Whether GPR17 is such an orphan receptor is still a matterof debate. Phylogenetically, GPR17 is closely related to the nucleotideP2Y receptors and the cysteinylleukotriene (CysLT1, CysLT2) receptors,with an amino acid sequence identity of between about 30 and about 35%,respectively.

Multiple-tissue Northern blot and RT-PCR analyses indicate a predominantexpression of GPR17 in the central nervous system (CNS) (Ciana et al.,2006, EMBO J 25(19): 4615; Blasius et al., 1998, J Neurochem 70(4):1357) and additionally in heart and kidney, i.e. organs typicallyundergoing ischemic damage. Two human GPR17 isoforms have beenidentified differing only by the length of their N-terminus. The shortGPR17 isoform encodes a 339 amino acid-residue protein with typicalrhodopsin type-seven transmembrane motifs. The long isoform encodes areceptor with a 28 amino acid longer N-terminus (Blasius et al., 1998).GPR17 is highly conserved among vertebrate species (˜90% identity ofamino acid sequence to both mouse and rat orthologs), which mayconstitute an advantageous feature for development of small moleculeligands and animal models in a drug discovery context.

In the original deorphaning report, GPR17 was identified as a dualreceptor for uracil nucleotides and cysteinyl-leukotrienes (cysLTs) LTC4and LTD4, respectively based on ³⁵SGTPyS binding and cAMP inhibitionassays as well as single cell calcium imaging (Ciana et al., 2006,ibid). Evidence for GPR17 functionality was provided in differentcellular backgrounds such as 1321N1, COS7, CHO, and HEK293 cells (Cianaet al., 2006, ibid). Subsequently, an independent study confirmedactivation of GPR17 by uracil nucleotides but failed to recapitulateactivation by CysLTs (Benned-Jensen and Rosenkilde, 2010, Br J Pharmacol, 159(5): 1092). Yet recent independent reports (Maekawa et al., 2009,PNAS 106(28), 11685; Qi et al., 2013, J Pharmacol Ther 347,1, 38; Hennenet al.,2013, Sci Signal 6, 298) suggested lack of GPR17 responsivenessto both uracil nucleotides and CysLTs across different cellularbackgrounds stably expressing GPR17 (1321N1, CHO, HEK293 cells). A novelregulatory role for GPR17 has also been proposed: GPR17—uponcoexpression with the CysLT1 receptor—rendered the CysLT1 receptorunresponsive to its endogenous lipid mediators LTC4 and LTD4. Clearly,additional in vitro investigations are required to probe GPR17pharmacology and function in more depth.

Drugs modulating the GPR17 activity may have neuroprotective,anti-inflammatory and anti-ischemic effects and may thus be useful forthe treatment of cerebral, cardiac and renal ischemia, and stroke (WO2006/045476), and/or for improving the recovery from these events(Bonfanti et al, Cell Death and Disease, 2017, 8, e2871).

GPR17 modulators are also thought to be involved in food uptake, insulinand leptin responses and are thus claimed to have a role in obesitytreatment (WO 2011/113032).

Moreover, there is strong evidence that GPR17 is involved in myelinationprocesses and that negative GPR17 modulators (antagonists or inverseagonists) can be valuable drugs for the treatment or alleviation ofmyelination disorders such as multiple sclerosis or spinal cord injury(Chen et al, Nature neuroscience 2009, 12(11):1398-406; Ceruti et al;Brain: a journal of neurology 2009 132(Pt 8):2206-18; Hennen et al, SciSignal, 6, 2013, 298;

Simon et al J Biol Chem 291, 2016, 705; Fumagalli et al,Neuropharmacology 104, 2016, 82). Activation of GPR17 has been shown toinhibit oligodendrocyte precursor cells (OPCs) maturation thuspreventing effective myelination (Simon et al, supra). Theidentification of potent and selective GPR17 antagonists or inverseagonists would thus be of significant relevance in the treatment ofmyelination disorders.

Several serious myelination diseases are known to be caused bydisturbances in myelination, either by a loss of myelin (usually calleddemyelination), and/or by a failure of the body to properly form myelin(sometimes called dysmyelination). The myelination diseases may beidiopathic or secondary to certain trigger events like e.g. traumaticbrain injury or viral infection. Myelination diseases may primarilyaffect the central nervous system (CNS) but may also concern theperipheral nervous system. Myelination diseases include, inter alia,multiple sclerosis, neuromyelitis optica (also known as Devic'sdisease), leucodystrophies, Guillain-Barrésyndrome, and many otherdiseases as described in more detail further below (see also e.g. Love,J Clin Pathol, 59, 2006, 1151, Fumagalli et al, supra).Neurodegenerative diseases such as Alzheimer's Disease, Huntington'sDisease, Parkinson's Disease, amyotropic lateral sclerosis (ALS) andmultiple system atrophy (MSA) have been also strongly associated withdecreased myelination recently (see e.g. Ettle et al, Mol Neurobiol 53,2016, 3046; Jellinger and Welling, Movement Disorders, 31, 2016; 1767;Kang et al, Nature Neurosci 6, 2013, 571; Bartzokis, Neurochem Res(2007) 32:1655).

Multiple Sclerosis (MS) is a chronic progressive disorder. It is aninflammatory autoimmune disease causing oligodendrocyte damage,demyelination and ultimately axonal loss, thus leading to a broadspectrum of signs and symptoms of a severe neurological disease, likee.g. fatigue, dizziness, mobility and walking issues, speech andswallowing difficulties, pain and others. MS takes several forms, withnew symptoms either occurring in isolated attacks (relapsing forms) orbuilding up over time (progressive forms). While certain symptoms maydisappear completely between isolated attacks, severe neurologicalproblems often remain, especially as the disease advances to a moreprogressive form. According to the Multiple Sclerosis Association ofAmerica, approximately 400,000 individuals have been diagnosed with MSin the United States and as many as 2.5 million worldwide, with anestimated 10,000 new cases diagnosed in the

United States annually. Multiple sclerosis is two to three times morecommon in women than in men.

There is no known causal treatment or cure for multiple sclerosis, ormany other myelination diseases. Treatments are usually symptomatic andtry to improve function after an attack and prevent new attacks, byaddressing the inflammatory component of the disease. Suchimmunomodulatory drugs are usually only modestly effective, inparticular if the disease is progressed, but can have side effects andbe poorly tolerated. Moreover, most of the available drugs, likeβ-interferons, glatiramer acetate, or therapeutic antibodies are onlyavailable in injectable form and/or only address the inflammatorycomponent of the disease but not demyelination directly Others drugs,like corticosteroids, show rather unspecific anti-inflammatory andimmunosupressive effects thus potentially leading to chronic sideeffects, such as manifested in Cushing's syndrome, for example.

A strong need therefore exists for a safe and effective drug for thetreatment of myelination diseases, like MS, preferably for a drug thatis suitable for oral administration. Ideally such a drug would reversethe demyelination process by decreasing demyelination and/or bypromoting remyelination of the impacted neurons. A chemical compoundwhich effectively decreases the GPR17 receptor activity could fulfilthese requirements.

However, only few chemical compounds are known that effectively modulateGPR17 activity.

WO 2005/103291 suggests the endogenous molecules 5 amino levulinic acid(5-ALA) and porphobilinogen (PBG) as activating ligands for GPR17,discloses analgesic effects of a GPR17 agonist and proposes the use ofGPR17 agonists for treating neuropathic pain and as tools in GPR17screening assays. However, the reported affinity of 5-ALA and PBG isquite low and the amounts needed in the assays are significant, namelyin the three digit micromolar range for 5-ALA or even in the mM rangefor PBG, which make both compounds not well suited for use in routinescreening assays or even for therapy. Moreover, PBG is a chemicallyunstable, reactive compound which rapidly decomposes after exposure toair and light, making it impractical to handle on a routine basis.Hence, these compounds do not offer a promising starting point todevelop therapeutically effective negative GPR17 modulators.

Montelukast and pranlukast were originally developed as leukotrienereceptor antagonists and were recently found to act on the GPR17receptor as well (Ciana et al, EMBO J. 2006, 25, 4615-4627). However,subsequent results in a functional assay were contradictory formontekulast (Hennen et al, 2013, ibid), while pharmacological inhibitionof GPR17 with pranlukast promotes differentiation of primary mouse(Hennen et al., 2013, ibid) and rat (Ou et al., J. Neurosci. 36, 2016,10560-10573) oligodendrocytes. Pranlukast even phenocopies the effect ofGPR17 depression in a lysolecithin model of focal demyelination becauseboth GPR17 knock-out and pranlukast-treated wild-type mice show anearlier onset of remyelination (Ou, ibid). These results stronglysupport the hypothesis that GPR17 inhibitors offer potential for thetreatment of human demyelinating diseases.

However, the affinity of montekulast and prankulast to GPR17 is only inthe high micromolar range (Kose et al, ACS Med. Chem. Lett. 2014, 5,326-330). Given the high protein binding of both compounds and theirpoor brain penetration, it is unlikely that they could reach high enoughfree concentrations to bind to GPR17 receptors in amounts suitable forhuman therapy. In addition, results obtained in vivo with thesecompounds are difficult to interpret due to their confounding highaffinity for CYSLT1 receptors.

U.S. Pat.No. 8,623,593 discloses certain indole-2-carboxylic acids asGPR17 agonists and their use in screening assays. However, thesederivatives are all potent agonists and are not suited to down-regulateGPR17 activity as needed in the treatment of myelination disorders suchas MS. Moreover, this class of GPR17 activators does not sufficientlypass the blood-brain barrier due to their easily ionizable carboxylgroups, and were thus no suitable lead compounds to develop negativeGPR17 modulators. See also Baqi et al, Med. Chem. Commun., 2014, 5, 86and Kose et al, 2014, ibid.

WO 2013/167177 suggests certain phenyltriazole and benzodiazepinecompounds as

GPR17 antagonists. However, the disclosed compounds were selected solelybased on in- silico screening results and no biological data at all wasprovided. The inventors of the present application were unable toconfirm the GPR17 antagonist modulating activity of any of purportedligands proposed by the authors of this former patent application sofar.

A need therefore exists to identify potent modulators, preferablynegative modulators, of GPR17 which are capable of effectivelydecreasing the GPR17 activity, preferably upon oral administration.

Mehra et al (Eur J Med Chem, 92, 2015, 78-90) disclose a variety ofcompounds with EColi acetyltransferase inhibiting activity, includingfour phenyl-substituted pyrrolo[2,3-b]pyridine-3-sulfonamides (compounds20 [N-(3,4-difluorophenyl 1 H-pyrrolo[2,3-b] pyridine-3-sulfonamide], 32[N-(3,5-dimethoxyphenyl 1H-pyrrolo[2,3-b]pyridine-3-sulfonamide], 37[N-(2,5-difluorophenyl 1H-pyrrolo[2,3-b]pyridine-3-sulfonamide] and 43[N-(3,5-difluorophenyl 1H-pyrrolo[2,3-b]pyridine-3-sulfonamide] of TableS7). These four azaindole compounds distinguish structurally from thepresently disclosed compounds in that the azaindole core in Mehra is notfurther substituted. Moreover, Mehra et al do not suggest any GPR17inhibiting property of these compounds and/or any utility of theircompounds for treating a myelination disorder. Instead, Mehra et aldisclose compounds as potential antibiotics.

FIGURES

FIG. 1 shows the expression of melin basic protein (MBP) as a marker ofoligodendrocyte maturation in a Western Blot assay. After administrationto oligodendrocyte progenitor cells (OPCs), the compounds of the presentinvention, in particular compounds I-112, I-185, I-108 and I-116,stimulated the MBP expression compared to vehicle alone.

FIG. 2 shows the effect of a compound of the present invention (I-116)on the length of myelin sheats expressed by OPCs. After administrationto OPCs, compound 1-116 induced the formation of longer myelin sheatscompared to OPS after addition of a vehicle alone.

FIG. 3 shows the plasma and brain exposure of a compound of the presentinvention, I-1, after intraperitoneal administration in mice.

FIG. 4 illustrates the distribution of PLP, a myelin marker, in tworelevant regions of the mice brain, Region 1 (FIG. 4.1) and Region 2(FIG. 4.2), after immunhistochemical staining with anti PLP-antibodies.This setup was used to measure the effects of compounds of the presentinvention in the cuprizone model (results shown in FIG. 5).

FIG. 5 shows the effect of a compound of the present invention (1-228)on the expression of PLP in mice during recovery from cuprizonetreatment, as measured by immunhistochemical staining. Following oraladministration of 1-228 at doses of 6mg/kg and 20 mg/kg to mice, themyelin-associated protein PLP reappeared significantly quicker incertain mice brain regions than after administration of vehicle only.

DESCRIPTION OF THE INVENTION

The present invention relates to a class of chemical compounds which arenegative GPR17 modulators.

These compounds have a general structure according to Formula I:

wherein

X1 is N or C(R7),

X2 is NH, S or O,

X3 is N or C(R12),

R4 is selected from hydrogen, methoxy and halogen including fluoro, andis preferably hydrogen,

R5 is selected from hydrogen, halogen, cyano, C₁₋₆ alkyl, C₂₋₃ alkenyl,C₂₋₃ alkynyl, C₁₋₆ alkoxy, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxycarbonyl, C₁₋₃alkylsulfinyl, and C₁₋₃alkylsulfonyl, wherein each alkyl or alkoxy mayoptionally be substituted one or more times selected from halogen, C₁₋₃alkoxy, cyano, azido, hydroxyl, C₁₋₃alkylamino and di(C₁₋₃alkyl)amino,and C₁₋₃ alkylaminocarbonyl (with preferred optional substitutions ofsaid alkyl and alkoxy groups being halogen and C₁₋₆ alkoxy), or R5 formsa ring together with R6 as described herein,

R6 is selected from hydrogen, hydroxy, halogen, cyano, azido, nitro,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl,C₃₋₆ cycloalkenyl, C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl,phenyl, C₅₋₁₀ heteroaryl, C₈₋₁₀ heterocyclyl , —ORx, —SRx, —SORx, SO₂Rx,-pentafluorosulfanyl , NRyRzz, —NRyCORx,—NRyCO₂Rx, —NRxCONRyRz,—NRySORx,—NRySO₂Rx, —CORx, —CO₂Rx,—CONRyRz, wherein each alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, cycloalkenyl, phenyl,heteroaryl or heterocyclyl group in R6 can be unsubstituted orsubstituted with one or more residue preferably selected from halogen,hydroxyl, oxo, cyano, azido, nitro, C₁₋₆ alkyl, halo(C₁₋₆)alkyl, C₁₋₆alkoxy(C₁₋₃) alkyl , C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, phenyl,C₅₋₁₀ (preferably C₅₋₆) heteroaryl, ORx, —SRx, —SORx, SO₂Rx,-pentafluorosulfanyl, NRyRz, —NRyCORx,—NRyCO₂Rx, —CORx, —CO₂Rx,—CONRyRz,

-   -   wherein Rx, Ry, Rz and Rzz are independently selected from        hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ cycloalkenyl, C₃₋₇        cycloalkyl(C₁₋₆)alkyl, phenyl, phenyl(C₁₋₆)alkyl, C₃₋₇        heterocycloalkyl, C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl, C₅₋₆        heteroaryl or heteroaryl(C₁₋₆)alkyl, any of which groups can be        unsubstituted or substituted with one or more substituents,        selected from those described above, and wherein Rzz is        preferably different from hydrogen,    -   or Ry and Rz, or Ry and Rzz together with the amino atom to        which they are both attached may form an aromatic or non        aromatic, unsubstituted or substituted C₅₋₆ heterocycle, wherein        any substituent is selected from the substituents described        above,

or R6 forms together with R5 or R7 and the carbon atoms to which theyare attached a 5 or 6 membered aromatic or non-aromatic ring which mayoptionally contain one or more heteroatoms selected from S, O, and N,and wherein said ring can be unsubstituted or substituted with one ormore substituents, wherein preferably (i) R6 forms together with R7 andthe carbon atoms to which R6 and R7 are attached, an unsubstituted orsubstituted phenyl, unsubstituted or substituted pyridyl, unsubstitutedor substituted cyclopentyl or unsubstituted or substituted cyclohexyl,wherein each substitution, if present, of a ring formed by R6 and R7, ispreferably selected from halogen, hydroxy, cyano, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₃ )alkyl,C₃₋₇ heterocycloalkyl(C₁₋₃)alkyl and C₁₋₆ alkoxy, wherein each alkyl oralkoxy can be unsubstituted or substituted with one or more substituentsselected from halogen, hydroxy, and unsubstituted or fluorinated C₁₋₃alkoxy, C₃₋₇ cycloalkyl, and C₃₋₇ heterocycloalkyl, wherein anysubstitution of phenyl, pyridyl, cyclopentyl and cyclohexyl arepreferably selected from fluoro, chloro, cyano, hydroxy, methyl,fluoromethyl, methoxy and fluoromethoxy,

or (ii) R6 forms together with R5 and the carbon atoms to which R6 andR5 are attached, a 1,3-dioxolane which may be unsubstituted orsubstituted with one or two substituents selected from fluoro andmethyl, or

R7, if present, is selected from hydrogen, halogen, cyano, azido, nitro,amino, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkynyl, C₂₋₆ alkenyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆alkylthio, C₁₋₃alkylcarbonylamino, C₁₋₆alkylaminocarbonyl, di(C₁₋₃)alkylaminocarbonyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkoxy, C₃₋₇ heterocycloalkyl, C₃₋₆ heterocycloalkoxy, phenyl,phenyloxy, phenyl(C₁₋₂)alkyl, phenyl(C₁₋₂) alkoxy, phenylsulfonyl,phenylsulfinyl, C₅₋₆ heteroaryl, C₅₋₆ heteroaryloxy, C₅₋₆heteroaryl(C₁₋₃)alkyl, C₅₋₆ heteroaryl(C₁₋₃)alkoxy,C₃₋₆cycloalkyl(C₁₋₂)alkyl, C₃₋₆ cycloalkyl(C₁₋₃)alkoxy, C₃₋₆heterocycloalkyl(C₁₋₂)alkyl, C₃₋₆ heterocycloalkyl(C₁₋₂)alkoxy, and,wherein each group in R7, in particular each alkyl, alkenyl, alkynyl,alkoxy, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl group, can beunsubstituted or substituted with one or more substituents selected fromhalogen, hydroxy, cyano, unsubstituted or halogenated C₁₋₆ alkyl andunsubstituted or halogenated C₁₋₆ alkoxy,

R8 is selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, C₁₋₃alkylsulfinyl, C₁₋₃alkylsulfonyl, C₁₋₃alkylthio, cyano,and halogen, wherein each alkyl or alkoxy can be unsubstituted orsubstituted with one or more substituents selected from halogen andunsubstituted or fluorinated C₁₋₃ alkoxy, or forms a ring systemtogether with R9, as described herein,

R9 is selected from hydrogen, halogen, cyano, azido, C₁₋₆ alkyl, C₁₋₆alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl and halogen, wherein each alkyl oralkoxy can be unsubstituted or substituted with one or more substituentsselected from halogen and unsubstituted or fluorinated C₁₋₃alkoxy,

or R9 forms together with R8 or R10 and the C atoms to which they areattached a 5 or 6 membered ring which can optionally be furthersubstituted and which may contain one or more ring forming heteroatomsselected from N, S, O, and Se;

wherein the ring formed by R9 together with R8 or R10 and the ring towhich they are attached form a bicyclic ring system preferably selectedfrom (a) 2,1,3-benzothiadiazole, (b) 2,1,3-benzoselenadiazole, (c)2,1,3-benzoxadiazole, (d) 1,3-benzothiazole, (e)1,3-benzoxazole whichmay be unsubstituted or may be partially hydrogenated and unsubstitutedor substituted with oxo, (f) 1,3-benzodioxole which may be unsubstitutedor substituted with one or two substituents selected from fluoro andmethyl, (g) benzothiophene, which may be unsubstituted or may bepartially hydrogenated and unsubstituted or substituted with one or twosubstituents selected from oxo, methyl or fluoro, wherein thebenzothiophene is preferably partially hydrogenated to1,3-dihydro-2-benzothiophen which is preferably substituted with twooxos to form 1,1-dioxido-2,3-dihydro-1-benzothiophen, which may beoptionally further substituted, (h) benzofuran, which may beunsubstituted or may be partially hydrogenated and unsubstituted orsubstituted with one or two groups selected from oxo, fluoro and methyl,preferably with one oxo group, wherein the benzofuran is preferablypartially hydrogenated to 1,3-dihydro-2-benzofuran which is preferablysubstituted with oxo to form 3-oxo-1,3 dihydrobenzofuran, which may beoptionally further substituted, e.g. with a methyl group, and (i)2,3-dihydro-1H-isoindol, which is preferably substituted with oxo togive 3-oxo-2,3-dihydro-1H-isoindol, which may be optionally furthersubstituted.

R10 is selected from hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, cyano, cyano(C₁₋₆)alkyl, cyano(C₁₋₆)alkyloxy,C₁₋₆alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylthio, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyloxy,C₃₋₆hetero cycloalkyl, C₃₋₆heterocycloalkyloxy, amino, azido,pentafluorosulfanyl, nitro, C₁₋₅ alkylcarbonylamino, C₁₋₅alkylaminocarbonyl, di(C₁₋₃)alkylaminocarbonyl, C₁₋₃alkylsulfinyl andC₁₋₃ alkylsulfonyl, wherein each alkyl, alkenyl, alkynyl or alkoxy canbe unsubstituted or substituted with one or more substituents selectedfrom halogen, C₁₋₆ alkoxy, halo(C₁₋₆)alkoxyhydroxy)C₁₋₆)alkoxy,optionally halogenated C₁₋₆ alkylthio, optionally halogenated C₁₋₃alkylcarbonyl, optionally halogenated C₁₋₃alkyloxycarbonyl, optionallyhalogenated C₁₋₃ alkylsulfonyl, optionally halogenatedC₁₋₃alkylsulfinyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylaminocarbonyl,di(C₁₋₃)alkylaminocarbonyl, hydroxy, cyano, nitro, oxo, C₃₋₆cycloalkyl,C₃₋₆cycloalkoxy, C₃₋₆heterocycloalkyl, C₃₋₆heterocycloalkoxy, phenyl,phenyloxy, and C₅₋₆heteroaryl, wherein any C₃₋₆cycloalkyl,C₃₋₆cycloalkoxy, C₃₋₆heterocycloalkyl, C₃₋₆heterocycloalkoxy, phenyl andheteroaryl may be unsubstituted or substituted with one or more residuesselected from halogen, hydroxy, hydroxymethyl, oxo, cyano, nitro, amino,optionally halogenated or hydroxylated C₁₋₃alkyl, optionallyhydroxylated or halogenated C₁₋₃alkoxy, optionally halogenatedC₁₋₃alkylcarbonyl and optionally halogenated C₁₋₃alkoxycarbonyl, anywherein the amino group may be substituted with one or two groupsselected from C₁₋₃alkyl, C₁₋₃alkylsulfonyl, C₁₋₃alkylcarbonyl, andC₁₋₃alkoxycarbonyl , or R10 forms a ring system together with R9, asdescribed herein,

R11 is selected from hydrogen, halogen, cyano, azido, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylsulfonyl, andC₁₋₆alkylsulfinyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein each alkyl oralkoxy can be unsubstituted or substituted with one or more substituentsselected from halogen and halogenated preferably fluorinated orunsubstituted C₁₋₃ alkoxy,

R12, if present, is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy andhalogen, wherein each alkyl or alkoxy can be unsubstituted orsubstituted with one or more substituents selected from halogen andhalogenated preferably fluorinated or unsubstituted C₁₋₃alkoxy, andpharmaceutically acceptable salts, solvates, isotopes and co-crystalsthereof.

In one embodiment, in the compounds of formula I,

X1 is N or C(R7),

X2 is NH or O,

X3 is N or C(R12),

R4 is selected from hydrogen and fluoro, and is preferably hydrogen,

R5 is selected from hydrogen, halogen, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₃alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃alkylsulfinyl, andC₁₋₃alkylsulfonyl, wherein each alkyl or alkoxy may optionally besubstituted one or more times selected from halogen, C₁₋₃alkoxy, C₂₋₃alkynyl, C₂₋₃ alkenyl, cyano, azido, hydroxyl, and optionally C₁₋₃alkylated amino (with preferred optional substitutions of said alkyl andalkoxy groups being halogen and C₁₋₆ alkoxy), or R5 forms a ringtogether with R6 as described herein,

R6 is selected from hydrogen, hydroxy, halogen, cyano, azido, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, C₃₋₆cycloalkenyl, C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl, phenyl,C₅₋₁₀ heteroaryl, C₈₋₁₀ heterocyclyl , —ORx, —SRx, —SORx, SO₂Rx,-pentafluorosulfanyl , NRyRzz, —NRyCORx,—NRyCO₂Rx, —NRxCONRyRz, —CORx,—CO₂Rx,—CONRyRz, wherein each alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, heterocycloalkyl, cycloalkenyl, phenyl, heteroaryl orheterocyclyl group in R6 can be unsubstituted or substituted with one ormore substituents preferably selected from halogen, hydroxyl, oxo,cyano, azido, nitro, C₁₋₆ alkyl, C₁₋₆alkoxy(C₁₋₃)alkyl , C₃₋₇cycloalkyl, C₃₋₇ heterocycloalkyl, phenyl, C₅₋₁₀ (preferably C₅₋₆)heteroaryl, ORx, —SRx, —SORx, SO₂Rx, -pentafluorosulfanyl, NRyRz,—NRyCORx,—NRyCO₂Rx, —CORx, —CO₂Rx, —CONRyRz,

-   -   wherein Rx, Ry, Rz and Rzz are independently selected from        hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ cycloalkenyl, C₃₋₇        cycloalkyl(C₁₋₆)alkyl, phenyl, phenyl(C₁₋₆)alkyl, C₃₋₇        heterocycloalkyl, C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl, C₅₋₆        heteroaryl or heteroaryl(C₁₋₆)alkyl, any of which groups can be        unsubstituted or substituted with one or more substituents,    -   or Ry and Rz, or Ry and Rzz together with the amino atom to        which they are both attached may form an aromatic or non        aromatic, unsubstituted or substituted C₅₋₆ heterocycle, wherein        Rzz is preferably different from hydrogen,

or R6 forms together with R5 or R7 and the carbon atoms to which theyare attached a 5 or 6 membered aromatic or non-aromatic ring which mayoptionally contain one or more heteroatoms selected from S, O, and N,and wherein said ring can be unsubstituted or substituted with one ormore substituents,

wherein preferably (i) R6 forms together with R7 and the carbon atoms towhich R6 and R7 are attached, an unsubstituted or substituted phenyl,unsubstituted or substituted pyridyl, unsubstituted or substitutedcyclopentyl or unsubstituted or substituted cyclohexyl, wherein eachsubstitution, if present, is selected from halogen, C₁₋₃ alkyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₃) alkyl, C₃₋₇heterocycloalkyl(C₁₋₃)alkyl, C₁₋₃ alkoxy, and C₁₋₃ alkoxy(C₁₋₃) alkyl,wherein each alkyl or alkoxy can be unsubstituted or substituted withone or more substituents selected from halogen and C₁₋₃ alkoxy, or (ii)R6 forms together with R5 and the carbon atoms to which R6 and R5 areattached, a 1,3-dioxolane which may be unsubstituted or substituted withone or two substituents selected from fluoro and methyl, or

R7 is selected from H, halogen, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆alkynyl, C₂₋₆ alkenyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₃₋₇ cycloalkyl, C₃₋₇heterocycloalkyl, phenyl, C₅₋₆ heteroaryl, wherein each alkyl, alkenyl,alkynyl or alkoxy group can be unsubstituted or substituted with one ormore substituents selected from halogen, and C₁₋₆ alkoxy,

R8 is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, and halogen,wherein each alkyl or alkoxy can be unsubstituted or substituted withone or more substituents selected from halogen and C₁₋₃ alkoxy, or formsa ring system together with R9, as described herein,

R9 is selected from hydrogen, halogen, cyano, azido, C₁₋₆ alkyl, C₁₋₆alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl and halogen, wherein each alkyl oralkoxy can be unsubstituted or substituted with one or more substituentsselected from halogen and C₁₋₃ alkoxy, or R9 forms together with R8 orR10 and the C atoms to which they are attached a 5 or 6 membered ringwhich can optionally be further substituted and which may contain one ormore ring forming heteroatoms selected from N, S, O, and Se;

wherein the ring formed by R9 together with R8 or R10 and the ring towhich they are attached are preferably selected from a bicyclic ringsystem selected from (a) 2,1,3-benzothiadiazole, (b)2,1,3-benzoselenadiazole, (c) 2,1,3-benzooxadiazole, (d)1,3-benzothiazole, (e)1,3-benzoxazole which may be unsubstituted or maybe partially hydrogenated and unsubstituted or substituted with oxo, (f)1,3-benzodioxole which may be unsubstituted or substituted with one ortwo substituents selected from fluoro and methyl, (g) benzothiophene,which may be unsubstituted or may be partially hydrogenated andunsubstituted or substituted with one or two substituents selected fromoxo, methyl or fluoro, or (h) benzofuran, which may be unsubstituted ormay be partially hydrogenated and unsubstituted or substituted with oneor two groups selected from oxo, fluoro and methyl, preferably with oneoxo group,

R10 is selected from hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, cyano, cyano(C₁₋₆) alkyl, C₁₋₆ alkylcarbonyl,C₁₋₆ alkoxycarbonyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylsulfinyl, azido,pentafluorosulfanyl, and nitro, wherein each alkyl, alkenyl, alkynyl oralkoxy can be unsubstituted or substituted with one or more substituentsselected from halogen and C₁₋₆ alkoxy, or R10 forms a ring systemtogether with R9, as described herein,

R11 is selected from hydrogen, halogen, cyano, azido, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylsulfonyl, andC₁₋₆ alkylsulfinyl, C₂₋₆ alkenyl, and

C₂₋₆ alkynyl, wherein each alkyl or alkoxy can be unsubstituted orsubstituted with one or more substituents selected from halogen andC₁₋₃alkoxy,

R12 is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy and halogen,wherein each alkyl or alkoxy can be unsubstituted or substituted withone or more substituents selected from halogen and C₁₋₃ alkoxy,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

In general, in the compounds of the present invention, where R8 and R9or R9 and R10 together form a bicyclic ring system such as2,1,3-benzothiadiazole, 2,1,3-benzoselenadiazole, 2,1,3-benzoxadiazole,dihydro(1,3)-benzoxazole, 1,3-benzothiazole, dihydrobenzothiophene,dihydrobenzofuran, dihydroisoindole, or 1,3-benzodioxole, and the like,as described herein, all phenyl moieties of these bicyclic groups cangenerally be substituted or unsubstituted as determined by therespective definition of the substituents R8, R10, R11 and R12 herein,whereas the annulated moieties of dihydrobenzothiophene,dihydrobenzofuran, dihydrobenzoxazole, or benzodioxole as formed by R8and R9, or R9 and R10, respectively, may be optionally substituted asexpressly defined herein. By way of non-limiting example, when a1,3-dihydro-2-benzofuran formed by R8 and R9 or R9 and R10 and the ringto which they are attached, is said to be optionally substituted withone or two groups selected from oxo, fluoro and methyl, then thisparticular oxo, fluoro or methyl substitution is a substitution of thering formed by R8 and R9 or R9 and R10, as the case may be, while thephenyl ring to which R8 and R9 or R9 and R10 are attached may beindependently further substituted as defined by the residues R8, R10,R11 and R12 herein. Likewise, if, for example, a benzodioxole groupwould be defined to be unsubstituted, this would refer to the ringformed by R8 and R9 or R9 and R10, whereas the phenyl ring to which theyare attached can be substituted in accordance with the definitions ofR8, R10, R11 and R12 herein.

In one preferred embodiment, in the compounds of Formula I, if R6 ishydrogen, and X1 is N, then R5 is different from hydrogen; in onepreferred embodiment R5 is iodo.

In one embodiment, R5, R6 and R7, if present, are not all hydrogen atthe same time

In one embodiment, R4, R5, R6 and R7, if present, are not all hydrogenat the same time

In one embodiment, R5, R6, R7 (if R7 is present), R8, R9, R10, and R11are not all hydrogen at the same time.

In one preferred embodiment of the present invention, in a compound ofFormula I, either

(a) X1 is CR7 and X2 is NH, S or O, or

(b) X1 is N and X2 is NH,

In one embodiment of the present invention, in a compound of Formula I,X2 is NH or O. In this embodiment, X1 is preferably CR7. In oneembodiment of the present invention, in a compound of Formula I, X2 isS. In this embodiment, X1 is preferably CR7

In one embodiment of the present invention, in a compound of Formula I,X2 is NH.

In one embodiment of the present invention, in a compound of Formula I,X2 is O. In this embodiment, X1 is preferably CR7

In one preferred embodiment of the present invention, in a compound ofFormula I, if X1 is N, then X2 is also N. In this embodiment, preferablyat least one of R4, R5 and R6 is different from hydrogen.

In a preferred embodiment, in the compounds of the present invention, atleast one of R8, R9, R10 and R11 is different from hydrogen. In anotherpreferred embodiment, at least one of R8, R9, R10 and R11 is differentfrom hydrogen and unsubstituted alkyl.

In one aspect, the items of the present invention do not include thecompounds N-3,4-difluorophenyl 1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,N-(3,5-dimethoxyphenyl 1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,N-(2,5-difluorophenyl 1H-pyrrolo[2,3-b]pyridine-3-sulfonamide, andN-(3,5-difluorophenyl 1H-pyrrolo[2,3-b]pyridine-3-sulfonamide per se,and for use as medicines or as active ingredient in a pharmaceuticalcomposition in general. In one aspect, the invention includes thesecompounds for use in the prevention and/or treatment of a myelinationdisorder as further defined herein, in particular in the preventionand/or treatment of multiple sclerosis and/or a method of treating orpreventing a GPR17 related disorder, in particular a myelinationdisorder such as, inter alia, multiple sclerosis.

In one particular aspect, the compounds of the present invention do notinclude [N-(4-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide],[N-[4-methoxy-3-(2-methoxyethoxy)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide],[N-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide],N-4-fluoro-2-methylphenyl 1 H-pyrrolo[2,3-b] pyridine-3-sulfonamide],[N-(2-chloro-4-fluorophenyl- 1 H-pyrrolo[2,3-b pyridine-3-sulfonamidesulfonamide], [N-(6-bromo-2-pyridinyl)1H-pyrrolo[2,3-b]pyridine-3-sulfonamide],[N-(5-chloro-2-pyridinyl)1H-pyrrolo[2,3-b]pyridine-3-sulfonamide],[N-(2,4-dichlorophenyI)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide],[N-(3-ethylphenyI)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide],N-(2,5-dimethylphenyI)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide],[N-[4-(ethylsuldonyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide],[N-(4-fluorophenyl)-1 H-pyrrolo [2,3-b]pyridine-3-sulfonamide],[N-(3-chloro-4-methoxyphenyl)-1 H-pyrrolo[2,3-b]pyridine-3-sulfonamide],[N-(2-ethyl-6-methylphenyl)1H-pyrrolo[2,3-b]pyridine-3-sulfonamide],[N-(2,4-difluorophenyl)1 H-pyrrolo[2,3-b]pyridine-3-sulfonamide, ],[N-[2-(trifluoromethyoxy)phenyl-]H-pyrrolo[2,3-b]pyridine-3-sulfonamide],[6-amino-N-(3-bromophenyl)-1H-Indole-3-sulfonamide],[6-amino-N-(2-fluorophenyl)-1 H-Indole-3-sulfonamide],[6-amino-N-(3-bromo-2-pyridinyl)-1H-Indole-3-sulfonamide],[N-(4-chloro-2-methylphenyl)-1 H-pyrrolo[2,3-b]pyridine-3-sulfonamide],and [N-(4-propylphenyl)- 1 H-pyrrolo[2,3-b]pyridine-3-sulfonamide perse, while in another aspect, the present invention encompasses thesespecific compounds for use (a) in therapy and/or diagnosis, (b) intreating or preventing a myelination disorder and/or any other diseaseor condition associated with a GPR17, such as a GPR17 dysfunction (c) asactive ingredient in a pharmaceutical composition along with optionalpharmaceutical carriers, and/or (d) in a method of treating orpreventing a disorder associated with GPR17, such as a GPR17dysfunction, in particular a myelination disorder such as, inter alia,multiple sclerosis .

In a further embodiment, in the compound of Formula I,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido,nitro, unsubstituted or substituted C₁₋₃ alkyl, preferably methyl,ethyl, isopropyl, mono-, di-, or trifluoromethyl, unsubstituted orsubstituted C₂₋₃ alkenyl, unsubstituted or substituted C₂₋₃ alkynyl,unsubstituted or substituted C₁₋₃ alkylcarbonyl, unsubstituted orsubstituted C₁₋₃ alkoxycarbonyl, unsubstituted or substituted C₁₋₃alkylsulfinyl preferably methylsulfinyl which may by further substitutedwith one to three fluoros, unsubstituted or substituted C₁₋₃alkylsulfonyl, preferably methylsulfonyl which may by furthersubstituted with one to three fluoros, unsubstituted or substitutedbenzylsulfonyl, unsubstituted or substituted benzylsulfinyl,unsubstituted or substituted C₃₋₇ cycloalkyl preferably cyclopropyl,unsubstituted or substituted C₃₋₇ cycloalkyl(C₁₋₃)alkyl preferablycyclopropylmethyl, unsubstituted or substituted C₃₋₇cycloalkyl(C₁₋₃)alkyloxy preferably cyclopropylmethoxy, unsubstituted orsubstituted C₃₋₇ heterocycloalkyl preferably tetrahydrofuranyl,unsubstituted or substituted C₃₋₇ heterocycloalkyl(C₁₋₃)alkyl,unsubstituted or substituted C₃₋₇ heterocycloalkyl(C₁₋₃)alkyloxypreferably tetrahydrofuranylmethoxy, unsubstituted or substituted C₁₋₃alkoxy preferably methoxy or ethoxy, each of which may be optionallysubstituted with one or more halogens preferably with fluoros,unsubstituted or substituted C₃₋₆ cycloalkoxy, unsubstituted orsubstituted C₃₋₆ heterocycloalkoxy, unsubstituted or substitutedC₁₋₃alkoxy(C₁₋₃)alkoxy, preferably methoxyethoxy, unsubstituted orsubstituted C₁₋₃alkoxy(C₁₋₃)alkyl, unsubstituted or substituted(C₃₋₆)cycloalkyl(C₁₋₃)alkoxy preferably cyclopropylmethoxy,unsubstituted or substituted (C₃₋₆)heterocycloalkyl(C₁₋₃)alkoxypreferably tetrahydrofuranylmethoxy, unsubstituted or substitutedphenyl, unsubstituted or substituted phenyloxy, unsubstituted orsubstituted thienyl, unsubstituted or substituted pyridyl, preferablyunsubstituted pyridyl, unsubstituted or substituted oxazole,unsubstituted or substituted thiazole, unsubstituted or substitutedisoxazole, unsubstituted or substituted phenyl(C₁₋₃)alkoxy preferablybenzyloxy, wherein each optional substitution in R6 is preferablyselected from fluoro, chloro, bromo, unsubstituted or fluorinatedmethyl, unsubstituted or fluorinated methoxy, hydroxy, and cyano, or

-   -   (i) R6 forms together with R7 and the carbon atoms to which R6        and R7 are attached, an unsubstituted or substituted phenyl,        unsubstituted or substituted pyridyl, unsubstituted or        substituted cyclopentyl or unsubstituted or substituted        cyclohexyl,        -   wherein each substitution, if present, is selected from            halogen, hydroxy, C₁₋₃alkyl, C₃₋₇ cycloalkyl,            C₃₋₇cycloalkyl(C₁₋₃) alkyl, C₃₋₇            heterocycloalkyl(C₁₋₃)alkyl, C₁₋₃alkoxy, and            C₁₋₃alkoxy(C₁₋₃)alkyl, wherein each alkyl or alkoxy can be            unsubstituted or substituted with one or more substituents            selected from halogen and C₁₋₃alkoxy, or    -   (ii) R6 forms together with R5 and the carbon atoms to which R6        and R5 are attached, a 1,3-dioxolane which may be unsubstituted        or substituted with one or two substituents selected from fluoro        and methyl,

wherein, preferably, if R6 is hydrogen, and X1 is N, then R5 ispreferably different from hydrogen and is more preferably iodo.

In a further embodiment, in the compound of Formula I,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido,unsubstituted or substituted C₁₋₃alkyl, preferably methyl, ethyl,isopropyl, or trifluoromethyl, unsubstituted or substituted C₂₋₃alkenyl, unsubstituted or substituted C₂₋₃alkynyl, unsubstituted orsubstituted C₁₋₃alkylcarbonyl, unsubstituted or substitutedC₁₋₃alkoxycarbonyl, unsubstituted or substituted C₁₋₃alkylsulfinylpreferably methylsulfinyl, unsubstituted or substitutedC₁₋₃alkylsulfonyl, preferably methylsulfonyl, unsubstituted orsubstituted C₃₋₇ cycloalkyl preferably cyclopropyl, unsubstituted orsubstituted C₃₋₇ cycloalkyl(C₁₋₃)alkyl preferably cyclopropylmethyl,unsubstituted or substituted C₃₋₇ heterocycloalkyl preferablytetrahydrofuranyl, unsubstituted or substituted C₃₋₇heterocycloalkyl(C₁₋₃)alkyl, unsubstituted or substituted C₁₋₃alkoxypreferably methoxy, unsubstituted or substituted C₃₋₆ cycloalkoxy,unsubstituted or substituted C₃₋₆ heterocycloalkoxy, unsubstituted orsubstituted C₁₋₃alkoxy(C₁₋₃)alkoxy, preferably methoxyethoxy,unsubstituted or substituted (C₃₋₆)cycloalkyl(C₁₋₃)alkoxy preferablycyclopropylmethoxy, unsubstituted or substituted(C₃₋₆)heterocycloalkyl(C₁₋₃)alkoxy preferably tetrahydrofuranylmethoxy,unsubstituted or substituted phenyl, unsubstituted or substitutedphenyloxy, unsubstituted or substituted thienyl, unsubstituted orsubstituted pyridyl, preferably unsubstituted pyridyl, unsubstituted orsubstituted oxazole, unsubstituted or substituted thiazole,unsubstituted or substituted isoxazole, unsubstituted or substitutedphenyl(C₁₋₃)alkoxy preferably benzyloxy, wherein each optionalsubstitution in R6 is preferably selected from fluoro, chloro, bromo,methyl, methoxy and cyano, or

-   -   (iii) R6 forms together with R7 and the carbon atoms to which R6        and R7 are attached, an unsubstituted or substituted phenyl,        unsubstituted or substituted pyridyl, unsubstituted or        substituted cyclopentyl or unsubstituted or substituted        cyclohexyl,        -   wherein each substitution, if present, is selected from            halogen, C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₃)            alkyl, C₃₋₇ heterocycloalkyl(C₁₋₃) alkyl, C₁₋₃alkoxy, and            C₁₋₃alkoxy(C₁₋₃)alkyl, wherein each alkyl or alkoxy can be            unsubstituted or substituted with one or more substituents            selected from halogen and C₁₋₃ alkoxy, or (    -   iv) R6 forms together with R5 and the carbon atoms to which R6        and R5 are attached, a 1,3-dioxolane which may be unsubstituted        or substituted with one or two substituents selected from fluoro        and methyl,

wherein, preferably, if R6 is hydrogen, and X1 is N, then R5 ispreferably different from hydrogen and is more preferably iodo.

In each occurance, where the compounds of the present invention containa R6 and a R7 group, which, together with the ring forming atoms of thebicyclic ring system to which they are attached, form another cycleselected from phenyl, pyridyl, cyclopentyl and cyclohexyl, this cycletogether with the bicyclic moiety to which it is annulated forms atricyclic moiety which is preferably selected from 1H-benzo[g]indol-3-yl, 1 H-pyrrolo[3,2-h]quinolin-3-yl,1,6,7,8-tetrahydrocyclopenta[g]indol-3y1, and 6,7,8,9-tetrahydro-1H-benzo[g]indol-3-yl. In one embodiment, any substitution of the1H-pyrrolo[3,2-h]quinolin-3-yl moiety is preferably in 8 position suchas to result in, for example, in8-(fluoromethyl)-1H-pyrrolo[3,2-h]quinoline.

In one preferred embodiment, in the compounds of Formula I,

X1 is N or C(R7),

X2 is NH, S or O, preferably NH,

X3 is N or C(R12),

R4 is selected from hydrogen, methoxy and halogen and is preferablyhydrogen or fluoro, most preferably hydrogen,

R5 is selected from hydrogen, halogen, cyano, C₁₋₃ alkyl, C₁₋₃ alkoxy,C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylsulfinyl, and C₁₋₃akylsulfonyl, wherein each alkyl or alkoxy may optionally be substitutedone or more times with a substituent selected from halogen, C₁₋₃ alkoxy,cyano, azido, C₁₋₃alkylamino and di(C₁₋₃alkyl)amino, preferably withmethoxy or halogen, or R5 forms a ring together with R6 as describedbelow,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido,nitro, unsubstituted or substituted C₁₋₃ alkyl, preferably methyl,ethyl, isopropyl, or mono-, di- or trifluoromethyl, unsubstituted orsubstituted C₁₋₃ alkoxy preferably methoxy, ethoxy, mono-, di- ortrifluoromethoxy, and mono-, di-or trifluoroethoxy, unsubstituted orsubstituted C₂₋₃ alkenyl, unsubstituted or substituted C₂₋₃ alkynyl,unsubstituted or substituted C₁₋₃ alkylcarbonyl, unsubstituted orsubstituted C₁₋₃alkoxycarbonyl, unsubstituted or substituted C₁₋₃alkylsulfinyl preferably methylsulfinyl, unsubstituted or substitutedC₁₋₃ alkylsulfonyl, preferably methylsulfonyl, unsubstituted orsubstituted benzylsulfonyl, unsubstituted or substituted benzylsulfinyl,unsubstituted or substituted C₃₋₇ cycloalkyl preferably cyclopropyl,unsubstituted or substituted C₃₋₇ cycloalkyl(C₁₋₃)alkyl preferablycyclopropylmethyl, unsubstituted or substituted C₃₋₇ heterocycloalkylpreferably tetrahydrofuranyl and oxetanyl, unsubstituted or substitutedC₃₋₇ heterocycloalkyl(C₁₋₃alkyl, unsubstituted or substituted C₃₋₆cycloalkoxy, unsubstituted or substituted C₃₋₆ heterocycloalkoxy,unsubstituted or substituted C₁₋₅alkoxy(C₁₋₅)alkyl, unsubstituted orsubstituted C₁₋₃alkoxy(C₁₋₃)alkoxy, preferably methoxyethoxy,unsubstituted or substituted (C₃₋₆)cycloalkyl(C₁₋₃)alkoxy preferablycyclopropylmethoxy, unsubstituted or substituted(C₃₋₆)heterocycloalkyl(C₁₋₃)alkoxy preferably tetrahydrofuranylmethoxy,unsubstituted or substituted phenyl, unsubstituted or substitutedphenyloxy, unsubstituted or substituted thienyl, unsubstituted orsubstituted pyridyl, preferably unsubstituted pyridyl, unsubstituted orsubstituted oxazole, unsubstituted or substituted thiazole,unsubstituted or substituted isoxazole, unsubstituted or substitutedphenyl(C₁₋₃)alkoxy preferably benzyloxy, wherein each optionalsubstitution in R6 is preferably selected from one or more of the groupconsisting of fluoro, chloro, bromo, unsubstituted or fluorinatedmethyl, unsubstituted or fluorinated methoxy, hydroxy, and cyano, or

-   -   (i) R6 forms together with R7 and the carbon atoms to which R6        and R7 are attached, an unsubstituted or substituted phenyl,        unsubstituted or substituted pyridyl, unsubstituted or        substituted cyclopentyl or unsubstituted or substituted        cyclohexyl,    -   wherein each substitution, if present, is selected from halogen,        hydroxy, cyano, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇        cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₃)alkyl, C₃₋₇        heterocycloalkyl(C₁₋₃)alkyl, C₁₋₆ alkoxy, and        C₁₋₆alkoxy(C₁₋₃)alkyl wherein each alkyl or alkoxy can be        unsubstituted or substituted with one or more substituents        selected from halogen and C₁₋₃alkoxy,    -   wherein each alkyl or alkoxy can be unsubstituted or substituted        with one or more substituents selected from halogen and        C₁₋₃alkoxy, or    -   (ii) R6 forms together with R5 and the carbon atoms to which R6        and R5 are attached, a 1,3-dioxolane which may be unsubstituted        or substituted with one or two substituents selected from fluoro        and methyl,

R7 is selected from H, halogen, cyano, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃alkylcarbonyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkylsulfonyl, C₁₋₃alkylsulfinyl, C₅₋₆ heteroaryl preferably isoxazol, and C₅₋₆heteroaryl(C₁₋₃)alkoxy preferably pyridylmethoxy, wherein each alkyl oralkoxy moiety can be substituted with one or more substituents,preferably with halogen, halo(C₁₋₆)alkoxy, or C₁₋₃alkoxy, and whereineach heteroaryl can be substituted with one or more substituents,preferably with halogen, methyl, hydroxy, or methoxy, or R7 forms a ringtogether with R6 as described herein,

R8 is selected from hydrogen, C₁₋₃alkyl, C₁₋₃alkoxy, cyano, and halogen,wherein each alkyl or alkoxy can be unsubstituted or substituted withone or more substituents selected from halogen, cyano and methoxy, or R8forms a ring system together with R9, as described herein,

R9 is selected from hydrogen, C₁₋₃alkyl, C₁₋₃alkoxy, fluoro, chloro,bromo and iodo, wherein each alkyl or alkoxy can be unsubstituted orsubstituted with one or more substituents selected from halogen andmethoxy,

or R9 forms together with R8 or R10 and the ring to which they areattached a bicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoselenadiazole, 2,1,3-benzoxadiazole, 1,3-benzothiazole,1,3-benzoxazole which may be unsubstituted or may be partiallyhydrogenated and substituted with oxo to form2-oxo-2,3-dihydro-1,3-benzoxazol-, 1,3-benzodioxole which may beunsubstituted or substituted with one or two substituents selected fromfluoro and methyl to preferably form 2,2-difluoro-1,3-benzodioxol,2,3-dihydrobenzothiophene, which may be unsubstituted or substitutedwith one or two oxo groups to preferably form1,1-dioxido-2,3-dihydro-1-benzothiophen, 1,3-dihydro-2-benzofuran, whichmay be unsubstituted or substituted with one or two groups selected fromoxo, fluoro and methyl, preferably with at least one oxo group topreferably form 3-oxo-1,3-dihydro-2-benzofuran or1-methyl-3-oxo-1,3-dihydro-2-benzofuran, and dihydroisoindol which maybe unsubstituted or substituted with one or more substituents selectedfrom oxo, fluoro and methyl and which preferably is3-oxo-2,3-dihydro-1H-isoindol,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₆ alkylpreferably C₁₋₃alkyl, C₁₋₅ alkoxy preferably C₁₋₃alkoxy, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₃₋₄ cycloalkyl, C₃₋₄ heterocycloalkyl, cyano,cyanomethyl, cyanomethoxy, C₁₋₃alkylcarbonyl, C₁₋₃alkoxycarbonyl, azido,pentafluorosulfanyl, and nitro, wherein each alkyl, alkenyl, alkynyl oralkoxy can be unsubstituted or substituted with one or more substituentsselected from halogen, unsubstituted or fluorinated C₁₋₃ alkoxy,unsubstituted or fluorinated C₁₋₃ alkoxycarbonyl, unsubstituted orfluorinated C₁₋₃ alkylcarbonyl, cyano, hydroxy, cyclopropyl and pyridyl,wherein the pyridyl may be optionally substituted with halogen,unsubstituted or fluorinated methyl and/or unsubstituted or fluorinatedmethoxy, and wherein any cycloalkyl or heterocycloalkyl can beunsubstituted or substituted with a group selected from halogen, cyano,hydroxy(C₁₋₂)alkyl, C₁₋₂alkoxy and C₁₋₂alkoxycarbonyl, or R10 forms aring system together with R8, as described herein,

R11 is selected from hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, fluoro, chloro,bromo, iodo, cyano, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxycarbonyl, whereineach alkyl and alkoxy can be unsubstituted or substituted with one ormore substituents selected from fluoro, chloro, bromo, iodo and C₁₋₃alkoxy,

R12, if present, is selected from hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy,fluoro, chloro, bromo, and iodo, wherein each alkyl and alkoxy can beunsubstituted or substituted with one or more substituents selected fromfluoro, chloro, bromo, iodo and C₁₋₃ alkoxy, wherein in one preferredembodiment if R6 is hydrogen, and X1 is N, then R5 is different fromhydrogen and is particularly preferably iodo,

wherein, in a preferred embodiment, at least one of R8, R9, R10 and R11is different from hydrogen, and more preferably at least one of R8, R9,R10 and R11 is also different from unsubstituted alkyl,

and wherein in another preferred embodiment, at least one of R5, R6 andR7, if present, is different from hydrogen, and pharmaceuticallyacceptable salts, solvates, isotopes and co-crystals thereof.

In one preferred embodiment, in the compounds of Formula I,

X1 is N or C(R7),

X2 is NH or O, preferably NH,

X3 is N or C(R12),

R4 is hydrogen or fluoro, preferably hydrogen,

R5 is selected from hydrogen, halogen, cyano, C₁₋₃ alkyl, C₁₋₃ alkoxy,C₁₋₃ alkylcarbonyl,

C₁₋₃ alkoxycarbonyl, C₁₋₃ alkylsulfinyl, and C₁₋₃ akylsulfonyl, whereineach alkyl or alkoxy may optionally be substituted one or more timeswith a substituent selected from halogen, C₁₋₃ alkoxy, cyano, azido, andan optionally alkylated amino group, preferably with methoxy or halogen,or R5 forms a ring together with R6 as described below,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido,unsubstituted or substituted C₁₋₃ alkyl, preferably methyl, ethyl,isopropyl, or trifluoromethyl, unsubstituted or substituted C₁₋₃ alkoxypreferably methoxy, unsubstituted or substituted C₂₋₃ alkenyl,unsubstituted or substituted C₂₋₃alkynyl, unsubstituted or substitutedC₁₋₃ alkylcarbonyl, unsubstituted or substituted C₁₋₃alkoxycarbonyl,unsubstituted or substituted C₁₋₃ alkylsulfinyl preferablymethylsulfinyl, unsubstituted or substituted C₁₋₃ alkylsulfonyl,preferably methylsulfonyl, unsubstituted or substituted C₃₋₇ cycloalkylpreferably cyclopropyl, unsubstituted or substituted C₃₋₇cycloalkyl(C₁₋₃)alkyl preferably cyclopropylmethyl, unsubstituted orsubstituted C₃₋₇ heterocycloalkyl preferably tetrahydrofuranyl,unsubstituted or substituted C₃₋₇ heterocycloalkyl(C₁₋₃)alkyl,unsubstituted or substituted C₃₋₆ cycloalkoxy, unsubstituted orsubstituted C₃₋₆ heterocycloalkoxy, unsubstituted or substitutedC₁₋₃alkoxy(C₁₋₃)alkoxy, preferably methoxyethoxy, unsubstituted orsubstituted (C₃₋₆)cycloalkyl(C₁₋₃)alkoxy preferably cyclopropylmethoxy,unsubstituted or substituted (C₃₋₆)heterocycloalkyl(C₁₋₃)alkoxypreferably tetrahydrofuranylmethoxy, unsubstituted or substitutedphenyl, unsubstituted or substituted phenyloxy, unsubstituted orsubstituted thienyl, unsubstituted or substituted pyridyl, preferablyunsubstituted pyridyl, unsubstituted or substituted oxazole,unsubstituted or substituted thiazole, unsubstituted or substitutedisoxazole, unsubstituted or substituted phenyl(C₁₋₃)alkoxy preferablybenzyloxy, wherein each optional substitution in R6 is preferablyselected from fluoro, chloro, bromo, methyl, methoxy and cyano, or

-   -   (i) R6 forms together with R7 and the carbon atoms to which R6        and R7 are attached, an unsubstituted or substituted phenyl,        unsubstituted or substituted pyridyl, unsubstituted or        substituted cyclopentyl or unsubstituted or substituted        cyclohexyl, wherein each substitution, if present, is selected        from halogen, C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₃)        alkyl, C₃₋₇ heterocycloalkyl(C₁₋₃)alkyl, C₁₋₃alkoxy, and        C₁₋₃alkoxy(C₁₋₃)alkyl, wherein each alkyl or alkoxy can be        unsubstituted or substituted with one or more substituents        selected from halogen and C₁₋₃ alkoxy, or    -   (ii) R6 forms together with R5 and the carbon atoms to which R6        and R5 are attached, a 1,3-dioxolane which may be unsubstituted        or substituted with one or two substituents selected from fluoro        and methyl,

R7 is selected from H, halogen, cyano, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃alkylcarbonyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkylsulfonyl, andC₁₋₃alkylsulfinyl, wherein each alkyl or alkoxy moiety can besubstituted with one or more substituents, preferably with halogen orC₁₋₃ alkoxy, or R7 forms a ring together with R6 as described herein,

R8 is selected from hydrogen, C₁₋₃alkyl, C₁₋₃ alkoxy, and halogen,wherein each alkyl or alkoxy can be unsubstituted or substituted withone or more substituents selected from halogen, cyano and methoxy, or R8forms a ring system together with R9, as described herein,

R9 is selected from hydrogen, C₁₋₃alkyl, C₁₋₃alkoxy, fluoro, chloro,bromo and iodo, wherein each alkyl or alkoxy can be unsubstituted orsubstituted with one or more substituents selected from halogen andmethoxy,

or R9 forms together with R8 or R10 and the ring to which they areattached a bicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoselenadiazole, 2,1,3-benzooxadiazole, 1,3-benzothiazole,1,3-benzoxazole which may be unsubstituted or may be partiallyhydrogenated and substituted with oxo, 1,3-benzodioxole which may beunsubstituted or substituted with one or two substituents selected fromfluoro and methyl, 2,3-dihydrobenzothiophene, which may be unsubstitutedor substituted with one or two oxo groups, and 1,3-dihydro-2-benzofuran,which may be unsubstituted or substituted with one or two groupsselected from oxo, fluoro and methyl, preferably with one oxo group,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cyano, cyanomethyl, C₁₋₃alkylcarbonyl, C₁₋₃ alkoxycarbonyl, azido, pentafluorosulfanyl, andnitro, wherein each alkyl, alkenyl, alkynyl or alkoxy can beunsubstituted or substituted with one or more substituents selected fromhalogen and C₁₋₃alkoxy, or R10 forms a ring system together with R8, asdescribed herein,

R11 is selected from hydrogen, C₁₋₃alkyl, C₁₋₃alkoxy, fluoro, chloro,bromo, iodo, C₁₋₃alkylcarbonyl, C₁₋₃ alkoxycarbonyl, wherein each alkyland alkoxy can be unsubstituted or substituted with one or moresubstituents selected from fluoro, chloro, bromo, iodo and C₁₋₃ alkoxy,

R12 is selected from hydrogen, C₁₋₃ alkyl, C₁₋₃alkoxy, fluoro, chloro,bromo, and iodo, wherein each alkyl and alkoxy can be unsubstituted orsubstituted with one or more substituents selected from fluoro, chloro,bromo, iodo and C₁₋₃alkoxy, wherein if R6 is hydrogen, and X1 is N, thenR5 is preferably different from hydrogen and is particularly preferablyiodo,

wherein, in a preferred embodiment, at least one of R8, R9, R10 and R11is different from hydrogen, and more preferably at least one of R8, R9,R10 and R11 is also different from unsubstituted alkyl, andpharmaceutically acceptable salts, solvates, isotopes and co-crystalsthereof.

A further embodiment relates to compounds of Formula I, wherein

X1 is N or C(R7),

X2 is NH, S, or O, preferably NH,

X3 is N or C(R12),

R4 is hydrogen or fluoro, preferably hydrogen,

R5 is selected from hydrogen, fluoro, chloro, bromo, iodo, unsubstitutedor fluorinated C₁₋₂ alkyl, preferably methyl or trifluoromethyl,unsubstituted or fluorinated C₁₋₂ alkyloxy, unsubstituted or fluorinatedC₁₋₂ alkylcarbonyl, unsubstituted or fluorinated C₁₋₂ alkyloxycarbonyl,C₁₋₂ alkylsulfinyl preferably methylsulfinyl, and C₁₋₂alkylsulfonylpreferably methylsulfonyl, wherein R5 preferably is preferably selectedfrom hydrogen, methyl,fluoro, chloro, bromo, and iodo, or R5 forms aring together with R6 as described herein,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido,unsubstituted or substituted C₁₋₃ alkyl, preferably methyl, ethyl,isopropyl, or trifluoromethyl, unsubstituted or fluorinated C₁₋₃alkylcarbonyl preferably acetyl, unsubstituted or fluorinated C₁₋₃alkoxycarbonyl preferably methoxycarbonyl, unsubstituted orfluorinated(C₁₋₃) alkylsulfinyl preferably methylsulfinyl, unsubstitutedor fluorinated (C₁₋₃)alkylsulfonyl preferably methylsulfonyl,unsubstituted or substituted C₃₋₆ cycloalkyl preferably cyclopropyl,unsubstituted or substituted C₃₋₆ cycloalkyl(C₁₋₃))alkyl preferablycyclopropylmethyl, unsubstituted or substituted C₃₋₆ heterocycloalkyl,unsubstituted or substituted C₃₋₆ cycloalkoxy, unsubstituted orsubstituted C₃₋₆ heterocycloalkoxy, unsubstituted or substituted C₁₋₃alkoxy preferably methoxy, ethoxy, fluoromethoxy, and fluoroethoxy,unsubstituted or substituted C₁₋₃alkoxy(C₁₋₃) alkoxy, preferablymethoxyethoxy, unsubstituted or substituted C₁₋₃alkoxy(C₁₋₃)alkyl,unsubstituted or substituted C₃₋₆ cycloalkyl(C₁₋₃)alkoxy preferablycyclopropylmethoxy, unsubstituted or substituted phenyl, unsubstitutedor substituted phenyl(C₁₋₃)alkoxy preferably benzyloxy, unsubstituted orsubstituted phenyloxy, unsubstituted or substitutedphenyl(C₁₋₃)alkylsulfonyl preferably benzylsulfonyl, unsubstituted orsubstituted phenyl(C₁₋₃)alkylsulfinyl preferably benzylsulfinyl,unsubstituted or substituted thienyl, pyridyl, oxazole, thiazole, andisoxazole, and wherein each optional substitution in R6 is preferablyselected from fluoro, chloro, unsubstituted or fluorinated methyl,unsubstituted or fluorinated methoxy, hydroxy, and cyano, provided thatif R6 is hydrogen, and X1 is N, then R5 is preferably different fromhydrogen and is preferably iodo, or

-   -   (i) R6 forms together with R7 and the carbon atoms to which R6        and R7 are attached, an unsubstituted or substituted phenyl, an        unsubstituted or substituted pyridyl, an unsubstituted or        substituted cyclopentyl or an unsubstituted or substituted        cyclohexyl,    -   wherein each substitution, if present, is selected from halogen,        hydroxy, methyl or methoxy, wherein each methyl or methoxy can        be unsubstituted or substituted with one or more substituents        selected from halogen preferably fluoro, and methoxy, or    -   (ii) R6 forms together with R5 and the carbon atoms to which R6        and R5 are attached, a 1,3-dioxolane which may be unsubstituted        or substituted with one or two substituents selected from fluoro        and methyl,

R7 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, C₁₋₃alkyl preferably methyl, C₁₋₃alkyloxy preferably methoxy,fluoro(C₁₋₃)alkyl preferably mono-, di-, or trifluoromethyl,fluoro(C₁₋₃)alkoxy preferably mono-, di- or trifluoromethoxy and mono-,di-, and trifluoroethoxy, unsubstituted or fluorinated C₁₋₃alkylcarbonyl, unsubstituted or fluorinated C₁₋₃alkoxycarbonyl,methylsulfinyl, methylsulfonyl, fluorinated methylsulfinyl, fluorinatedmethylsulfonyl, substituted or unsubstituted C₅₋₆ heteroaryl,substituted or unsubstituted C₅₋₆ heteroaryloxy, and C₅₋₆heteroarylmethoxy, wherein the heteroaryl is preferably selected frompyridyl, oxazol and isoxazol, and wherein the heteroaryl may besubstituted with one or more substituents selected from halogen,unsubstituted or fluorinated methyl, unsubstituted or fluorinatedmethoxy, or R7 forms a ring together with R6 as described herein,

R8 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano,C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃)alkoxy, C₁₋₃ alkylpreferably methyl, and fluoro(C₁₋₃)alkyl preferably trifluoromethyl, orR8 forms a ring system together with R10, as described herein,

R9 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyloxypreferably methoxy, fluoro(C₁₋₃)alkoxy, C₁₋₃ alkyl preferably methyl,cyano, and fluoro(C₁₋₃)alkyl preferably trifluoromethyl, and ispreferably hydrogen, fluoro, chloro, or bromo, or R9 forms together withR8 and the ring to which they are attached a bicyclic ring systemselected from 2,1,3-benzothiadiazole, 2,1,3-benzoselenadiazole,2,1,3-benzoxadiazole, 1,3-benzoxazole which may be unsubstituted or maybe partially hydrogenated and substituted with oxo (to give2-oxo-2,3-dihydro-1,3-benzoxazole) and 1,3-benzodioxole, which isoptionally substituted with one or two fluoros, or R9 forms togetherwith R10 and the ring to which they are attached a bicyclic ring systemselected from 2,1,3-benzothiadiazole, 2,1,3-benzoselenadiazole,2,1,3-benzoxadiazole, 1,3-benzothiazole, 3-oxo-2,3-dihydro-1H-isoindol,2,3-dihydro-1-benzothiophene, which is substituted with one or two oxo(preferably substituted with two oxo to give1,1-dioxo-2,3-dihydro-1-benzothiophene), 3-oxo-1,3-dihydro-2-benzofuran,which is optionally substituted with methyl to give1-methyl-3-oxo-1,3-dihydro-2-benzofuran, and 1,3-benzodioxole, which isoptionally substituted with one or two fluoros,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyl,halo(C₁₋₃)alkyl, preferably fluoro(C₁₋₃)alkyl, particularlytrifluoromethyl, C₂₋₃ alkynyl, C₁₋₃ alkyloxy, halo(C₁₋₃) alkyloxy,preferably fluoro(C₁₋₂)alkoxy, cyclopropylcyano, cyanomethyl,cyanoethyl, unsubstituted or fluorinated C₁₋₃ alkylcarbonyl preferablyacetyl, unsubstituted or fluorinated C₁₋₃ alkoxycarbonyl preferablymethoxycarbonyl, azido, pentafluorosulfanyl, and nitro, wherein eachalkyl, cyclopropyl, alkoxy, alkenyl or alkynyl in R10, unless otherwisespecified, may be optionally further substituted with one or moresubstituents selected from fluoro, chloro, cyano, hydroxy, C₁₋₃ alkoxypreferably methoxy, halo C₁₋₃ alkoxy, and unsubstituted or fluorinatedC₁₋₃ alkoxycarbonyl, wherein each alkyl and alkoxy may also besubstituted with cyclopropyl which can be optionally substituted as7defined above, or R10 forms a ring system together with R9, asdescribed herein,

R11 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkylpreferably methyl, fluoro(C₁₋₃)alkyl preferably fluorinated methyl suchas trifluoromethyl, C₁₋₃ alkyloxy preferably methoxy, fluoro(C₁₋₃)alkoxypreferably fluoro(C₁₋₂)alkoxy, unsubstituted or fluorinated C₁₋₃alkylcarbonyl preferably acetyl, unsubstituted or fluorinated C₁₋₃alkoxycarbonyl preferably methoxycarbonyl, and cyano, and is morepreferably hydrogen, fluoro, chloro or bromo,

R12, if present, is selected from hydrogen, fluoro, chloro, bromo, iodo,C₁₋₃ alkyl preferably methyl, fluoro(C₁₋₃)alkyl preferablytrifluoromethyl, C₁₋₃ alkyloxy preferably methoxy, fluoro(C₁₋₃) alkoxypreferably fluoro(C₁₋₂)alkoxy, and cyano and is more preferablyhydrogen, fluoro, chloro, or bromo.

wherein, in a preferred embodiment, at least one of R8, R9, R10 and R11is different from hydrogen, and more preferably at least one of R8, R9,R10 and R11 is also different from unsubstituted alkyl,

and wherein in another preferred embodiment, at least one of R5, R6 andR7, if present, is different from hydrogen,and wherein in one preferredembodiment, if X1 is N, then X2 in NH,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

A further embodiment relates to compounds of Formula I,

wherein

X1 is N or C(R7),

X2 is NH or O, preferably NH,

X3 is N or C(R12),

R4 is hydrogen,

R5 is selected from hydrogen, fluoro, chloro, bromo, iodo, unsubstitutedor fluorinated C₁₋₂ alkyl, preferably methyl or trifluoromethyl,unsubstituted or fluorinated C₁₋₂ alkyloxy, unsubstituted or fluorinatedC₁₋₂ alkylcarbonyl, unsubstituted or fluorinated C₁₋₂ alkyloxycarbonyl,C₁₋₂ alkylsulfinyl preferably methylsulfinyl, and C₁₋₂alkylsulfonylpreferably methylsulfonyl, preferably hydrogen, methyl or iodo, or R5forms a ring together with R6 as described herein,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido,unsubstituted or substituted C₁₋₃ alkyl, preferably methyl, ethyl,isopropyl, or trifluoromethyl, unsubstituted or fluorinated C₁₋₃alkylcarbonyl preferably acetyl, unsubstituted or fluorinated C₁₋₃alkoxycarbonyl preferably methoxycarbonyl, (C₁₋₃) alkylsulfinylpreferably methylsulfinyl, (C₁₋₃)alkylsulfonyl preferablymethylsulfonyl, C₃₋₆ cycloalkyl preferably cyclopropyl, C₃₋₆cycloalkyl(C₁₋₃))alkyl preferably cyclopropylmethyl, C₃₋₆heterocycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆ heterocycloalkoxy,unsubstituted or substituted C₁₋₃ alkoxy preferably methoxy,unsubstituted or substituted C₁₋₃alkoxy(C₁₋₃) alkoxy, preferablymethoxyethoxy, C₃₋₆ cycloalkyl(C₁₋₃)alkoxy preferablycyclopropylmethoxy, unsubstituted or substituted phenyl, unsubstitutedor substituted phenyl(C₁₋₃)alkoxy preferably benzyloxy, unsubstituted orsubstituted phenyloxy, unsubstituted or substituted thienyl, pyridyl,oxazole, thiazole, and isoxazole, and wherein each optional substitutionin R6 is preferably selected from fluoro, chloro, methyl, methoxy, andcyano, provided that if R6 is hydrogen, and X1 is N, then R5 ispreferably different from hydrogen and is preferably iodo, or

-   -   (i)R6 forms together with R7 and the carbon atoms to which R6        and R7 are attached, an unsubstituted or substituted phenyl, an        unsubstituted or substituted pyridyl, an unsubstituted or        substituted cyclopentyl or an unsubstituted or substituted        cyclohexyl,    -   wherein each substitution, if present, is selected from halogen,        methyl or methoxy, wherein each methyl or methoxy can be        unsubstituted or substituted with one or more substituents        selected from fluoro and methoxy, or    -   (ii) R6 forms together with R5 and the carbon atoms to which R6        and R5 are attached, a 1,3-dioxolane which may be unsubstituted        or substituted with one or two substituents selected from fluoro        and methyl,

R7 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, C₁₋₃alkyl, C₁₋₃ alkyloxy, fluoro(C₁₋₃)alkyl preferably trifluoromethyl,fluoro(C₁₋₃)alkoxy preferably trifluoromethoxy, unsubstituted orfluorinated C₁₋₃ alkylcarbonyl, unsubstituted or fluorinated C₁₋₃alkoxycarbonyl, methylsulfinyl, and methylsulfonyl, or R7 forms a ringtogether with R6 as described herein,

R8 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyloxypreferably methoxy, fluoro(C₁₋₃)alkoxy, C₁₋₃ alkyl preferably methyl,and fluoro(C₁₋₃)alkyl preferably trifluoromethyl, or R8 forms a ringsystem together with R10, as described herein,

R9 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyloxypreferably methoxy, fluoro(C₁₋₃)alkoxy, C₁₋₃ alkyl preferably methyl,cyano, and fluoro(C₁₋₃)alkyl preferably trifluoromethyl, and ispreferably hydrogen, fluoro, chloro, or bromo, or R9 forms together withR8 and the ring to which they are attached a bicyclic ring systemselected from 2,1,3-benzothiadiazole, 2,1,3-benzoselenadiazole,2,1,3-benzooxadiazole, 1,3-benzoxazole which may be unsubstituted or maybe partially hydrogenated and substituted with oxo (to give2-oxo-2,3-dihydro-1,3-benzoxazole) and 1,3-benzodioxole, which isoptionally substituted with one or two fluoros, or R9 forms togetherwith R10 and the ring to which they are attached a bicyclic ring systemselected from 2,1,3-benzothiadiazole, 2,1,3-benzoselenadiazole,2,1,3-benzooxadiazole, 1,3-benzothiazole, 2,3-dihydro-1-benzothiophene,which is substituted with one or two oxo (preferably substituted withtwo oxo to give 1,1-dioxo-2,3-dihydro-1-benzothiophene),3-oxo-1,3-dihydro-2-benzofuran, and 1,3-benzodioxole, which isoptionally substituted with one or two fluoros,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyl,halo(C₁₋₃)alkyl, preferably fluoro(C₁₋₃)alkyl, particularlytrifluoromethyl, C₂₋₃ alkynyl, C₁₋₃ alkyloxy, halo(C₁₋₃) alkyloxy,preferably fluoro(C₁₋₂)alkoxy, cyano, cyanomethyl, unsubstituted orfluorinated C₁₋₃ alkylcarbonyl preferably acetyl, unsubstituted orfluorinated C₁₋₃ alkoxycarbonyl preferably methoxycarbonyl, azido,pentafluorosulfanyl, and nitro, or R10 forms a ring system together withR9, as described herein,

R11 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkylpreferably methyl, fluoro(C₁₋₃)alkyl preferably trifluoromethyl, C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃) alkoxy preferablyfluoro(C₁₋₂)alkoxy, unsubstituted or fluorinated C₁₋₃ alkylcarbonylpreferably acetyl, unsubstituted or fluorinated C₁₋₃ alkoxycarbonylpreferably methoxycarbonyl, and cyano, and is more preferably hydrogen,fluoro, chloro or bromo,

R12 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkylpreferably methyl, fluoro(C₁₋₃)alkyl preferably trifluoromethyl, C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃) alkoxy preferablyfluoro(C₁₋₂)alkoxy, and cyano and is more preferably hydrogen, fluoro,chloro, or bromo.

wherein, in a preferred embodiment, at least one of R8, R9, R10 and R11is different from hydrogen, and more preferably at least one of R8, R9,R10 and R11 is also different from unsubstituted alkyl,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

In one preferred embodiment, in the compounds of Formula I as describedherein, if X2 is O, then X1 is C(R7).

A further embodiment relates to compounds of Formula I,

wherein

X1 is N or C(R7),

X2 is NH, S or O provided that if X1 is N, then X2 is preferably also N,

X3 is N or C(R12),

R4 is hydrogen or fluoro, preferably hydrogen,

R5 is selected from hydrogen, methyl, fluoro, chloro and bromo,

or R5 forms a ring together with R6 as described herein,

R6 is selected from hydrogen, halogen, cyano, nitro, azido, C₁₋₃ alkyl,C₁₋₃alkylsulfinyl preferably methylsulfinyl, C₁₋₃alkylsulfonylpreferably methylsulfonyl, cyclopropyl, cyclopropylmethyl,cyclopropyloxy, C₁₋₃ alkoxy preferably methoxy or ethoxy, phenyl,phenyloxy, benzyl, phenyl(C₁₋₃)alkoxy preferably benzyloxy,benzylsulfinyl, benzylsulfonyl, tetrahydrofuranyl, and a 5-6 memberedheteroaryl, preferably selected from thienyl, pyridyl, oxazole, andisoxazole, and wherein each alkyl, alkoxy, cyclopropyl,tetrahydrofuranyl, phenyl or heteroaryl group can be optionallysubstituted one or more times with substituents selected from fluoro,chloro, hydroxy, unsubstituted or fluorinated C₁₋₂ alkyl, unsubstitutedor fluorinated C₁₋₂ alkoxy, and cyano, or

-   -   (i) R6 forms together with R7 and the carbon atoms to which R6        and R7 are attached, an unsubstituted or substituted phenyl, an        unsubstituted or substituted pyridyl, an unsubstituted or        substituted cyclopentyl or an unsubstituted or substituted        cyclohexyl,    -   wherein each substitution, if present, is selected from halogen,        hydroxy, methyl or methoxy, wherein each methyl or methoxy can        be unsubstituted or substituted with one or more substituents        selected from halogen, preferably fluoro, and methoxy, or    -   (ii) R6 forms together with R5 and the carbon atoms to which R6        and R5 are attached, a 1,3-dioxolane which may be unsubstituted        or substituted with one or two substituents selected from fluoro        and methyl,

R7 is selected from hydrogen, halogen, cyano, C₁₋₃ alkyl, C₁₋₃alkyloxy,fluoro(C₁₋₃)alkyl preferably mono-, di-, and trifluoromethyl,fluoro(C₁₋₃)alkoxy preferably mono-, di-, and trifluoromethoxy or mono-,di-, and trifluoroethoxy, unsubstituted or fluorinated methylsulfinyl,unsubstituted or fluorinated methylsulfonyl, C₅₋₆ heteroaryl, C₅₋₆heteroaryloxy, C₅₋₆ heteroarylmethyl and C₅₋₆ heteroarylmethoxy, whereinthe heteroaryl (in each occurance in R7) is preferably selected frompyridyl, oxazol and isoxazol, and wherein the heteroaryl isunsubstituted or substituted with one or more substituents selected fromhalogen, cyano, unsubstituted or fluorinated methyl, and unsubstitutedor fluorinated methoxy, or R7 forms a ring together with R6 as describedherein,

R8 is selected from hydrogen, fluoro, chloro, bromo, C₁₋₃ alkyloxypreferably methoxy, fluoro(C₁₋₃)alkoxy preferably fluoromethoxy, andunsubstituted or fluorinated C₁₋₃alkyl preferably fluoromethyl, or R8forms a ring system together with R10, as described herein,

R9 is selected from hydrogen, fluoro, chloro, methoxy, fluromethoxy,methyl and fluoromethyl,

or R9 forms together with R8 and the ring to which they are attached abicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoselenadiazole, 2,1,3-benzoxadiazole, 1,3-benzoxazole whichmay be unsubstituted or may be partially hydrogenated and substitutedwith oxo (to give 2-oxo-2,3-dihydro-1,3-benzoxazole) and1,3-benzodioxole, which is optionally substituted with one or twofluoros, or R9 forms together with R10 and the ring to which they areattached a bicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoselenadiazole, 2,1,3-benzoxadiazole, 1,3-benzothiazole,3-oxo-2,3-dihydro-1H-isoindol, 2,3-dihydro-1-benzothiophene, which issubstituted with one or two oxo (preferably substituted with two oxo togive 1,1-dioxo-2,3-dihydro-1-benzothiophene),3-oxo-1,3-dihydro-2-benzofuran, which is optionally substituted withmethyl to give 1-methyl-3-oxo-1,3-dihydro-2-benzofuran, and1,3-benzodioxole, which is optionally substituted with one or twofluoros,

R10 is selected from hydrogen, halogen, cyano, azido,pentafluorosulfanyl, nitro, C1-3 alkyl, C₂-₃ alkenyl, C₂-₃ alkynyl, C₁₋₃alkyloxy, C₁₋₃ alkylcarbonyl preferably acetyl, C₃₋₆cycloalkylpreferably cycloalkyl, C₃₋₆ cycloalkyloxy preferably cycloalkyloxy,C₃₋₆hetero cycloalkyl, C₃₋₆heterocycloalkyloxy, wherein each cycloalkylis optionally substituted by one or more substituents selected fromfluoro, cyano, unsubstituted or fluorinated C₁₋₂alkoxy, andunsubstituted or fluorinated C₁₋₂alkoxycarbonyl, and wherein each alkyl,alkoxy, alkenyl or alkynyl in R10 may be optionally further substitutedwith one or more substituents selected from cyclopropyl, halogenpreferably fluoro, cyano, hydroxy, C₁₋₃alkoxy, halo(C₁₋₃)alkoxypreferably fluoro(C₁₋₃)alkoxy, unsubstituted or fluorinated C₁₋₃alkylcarbonyl, and unsubstituted or fluorinated C₁₋₃ alkoxycarbonyl, orR10 forms a ring system together with R9, as described herein,

R11 is selected from hydrogen, fluoro, chloro, bromo, C₁₋₃ alkylpreferably methyl, fluoro(C₁₋₃)alkyl preferably fluoromethyl,C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃ alkoxy preferablyfluoromethoxy, and cyano,

R12, if present, is selected from hydrogen, fluoro, chloro, bromo,methyl, fluoromethyl, methoxy and fluoromethoxy, wherein preferably, R12is hydrogen or fluoro,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof;

wherein, in a preferred embodiment, at least one, more preferably two ofR8, R10 and R11 are different from hydrogen, and more preferably atleast one of R8, R10 and R11 is also different from unsubstituted alkyl,

and wherein in another preferred embodiment, at least one of R5, R6 andR7, if present, is different from hydrogen,

A further embodiment relates to compounds of Formula I, wherein

X1 is N or C(R7),

X2 is NH, S or O, preferably NH or 0,

X3 is N or C(R12),

R4 is hydrogen,

R5 is selected from hydrogen, fluoro, chloro and bromo,

R6 is selected from fluoro, chloro, bromo, iodo, cyano, azido, amino,nitro, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, ethenyl,ethynyl, propargyl, methylsulfinyl, methylsulfonyl, cyclopropyl,cyclopropyloxy, cyclopropylmethyl, methoxy, ethoxy, propoxy,methoxyethoxy, ethoxymethoxy, cyclopropylmethoxy, oxetanyl,oxetanylmethoxy, tetrahydrofuranyl, tetrahydrofuranylmethoxy, phenyl,benzyloxy, phenyloxy, benzylsulfinyl, thienyl, pyridyl, oxazole,thiazole, and isoxazole, wherein each phenyl, thienyl, pyridyl, oxazol,thiazole and isoxazol can be optionally substituted one or more times,preferably with a substitution selected from halogen, methoxy, andmethyl, and wherein each alkyl, alkenyl, alkynyl and alkoxy group can besubstituted one or more times with halogen preferably fluoro, methoxy,fluoromethoxy, and hydroxy,

or R6 forms together with R7 and the carbon atoms to which R6 and R7 areattached, a ring selected from phenyl, pyridyl, cyclohexyl, andcyclopentyl, each of which can be unsubstituted or further substitutedwith one or more residues selected from halogen, hydroxy, unsubstitutedor fluorinated methyl, and unsubstituted or fluorinated methoxy,

R7 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano,methylsulfinyl, methylsulfonyl, methoxy, fluoromethoxy, fluoroethoxy,methyl, fluoromethyl, and fluoroethyl, or R7 forms a ring together withR6 as described herein,

R8 is selected from hydrogen, fluoro, chloro, bromo, iodo, methoxy,fluoromethoxy, cyano, methyl, and fluoromethyl, or R8 forms a ringsystem together with R10, as described herein,

R9 is selected from hydrogen, fluoro and chloro and is preferablyhydrogen,

or R9 forms together with R8 or R10 and the ring to which they areattached a bicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoxadiazole, 2-oxo-2,3-dihydro-1,3-benzoxazole and1,3-benzodioxole, which is optionally substituted with two fluoros, orR9 forms together with R10 and the ring to which they are attached abicyclic ring system selected from 3-oxo-2,3-dihydro-1H-isoindol,2,3-dihydro-1-benzothiophene, which is substituted with one or two oxo(preferably substituted with two oxo to give1,1-dioxo-2,3-dihydro-1-benzothiophene), and optionally methylated3-oxo-1,3-dihydro-2-benzofuran,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl,ethyl, n-propyl, isopropyl, ethenyl, n-propenyl, isopropenyl, ethynyl,propargyl, fluoro(C₁₋₃)alkyl preferably trifluoromethyl, methoxy,ethoxy, propoxy, fluoro(C₁₋₃)alkoxy C₁₋₃alkoxy(C₁₋₃)alkyl,C₁₋₃alkoxy(C₁₋₃)alkoxy, C₁₋₃alkoxy(C₁₋₃ )alkenyl,C₁₋₃alkoxy(C₁₋₃)alkynyl, C₁₋₃alkoxycarbonyl(C₁₋₃)alkyl,C₁₋₃alkylcarbonyl(C₁₋₃)alkyl, C₁₋₃ alkylcarbonyl(C₁₋₃)alkyloxy, cyano,acetyl, azido, nitro, pentafluorosulfanyl, cyclopropyl, cyclopropyloxy,cyclopropylmethoxy, and C₁₋₃ alkoxycarbonyl including methoxycarbonyl,wherein each alkyl, alkenyl, alkynyl and alkoxy group in R10 can beunsubstituted or substituted with one or more residues selected fromhalogen preferably fluoro, cyano and/or hydroxy, and wherein thecyclopropyl is optionally substituted with one or more residues selectedfrom cyano, optionally fluorinated C₁₋₂ alkoxy and optionallyfluorinated C₁₋₂alkoxycarbonyl, or R10 forms a ring system together withR9, as described herein,

R11 is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl,fluoromethyl, methoxy and fluoromethoxy,

R12, if present, is selected from hydrogen, fluoro, chloro, and bromo,and is preferably hydrogen or fluoro.

wherein, in a preferred embodiment, at least one of R8, R9, R10 and R11,more preferably at least one or at least two, most preferably all of R8,R10 and R11, are different from hydrogen and at least one, preferably atleast two of R8, R10 and R11, are preferably also different fromunsubstituted alkyl, and pharmaceutically acceptable salts, solvates,isotopes and co-crystals thereof.

A further embodiment relates to compounds of Formula I, wherein

X1 is N or C(R7),

X2 is NH, S or O, preferably NH or O,

X3 is N or C(R12),

R4 is hydrogen,

R5 is selected from hydrogen, fluoro, chloro and bromo,

R6 is selected from fluoro, chloro, bromo, azido, nitro, methyl, ethyl,isopropyl, trifluoromethyl, methylsulfinyl, methylsulfonyl, cyclopropyl,methoxy, phenyl, benzyloxy, phenylsulfinyl, benzylsulfinyl,thiophen-2-yl, and thiophen-3-yl, wherein each alkyl and alkoxy group inR6 can be substituted one or more times with fluoro, methoxy, cyano andhydroxy,

or R6 forms together with R7 and the carbon atoms to which R6 and R7 areattached, a ring selected from phenyl, pyridyl, cyclohexyl, andcyclopentyl, each of which can be optionally substituted one or moretimes with a group selected from methyl, fluorinated methyl, methoxy,fluorinated methoxy and fluoro,

R7 is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl,ethyl, methylsulfonyl, methylsulfinyl, methoxy, ethoxy, mono-, di-, andtrifluoromethoxy, mono-, di-, and trifluoroethoxy, mono-, di-, andtrifluoromethyl, mono-, di-, and trifluoroethyl, or R7 forms a ringtogether with R6 as described herein,

R8 is selected from hydrogen, fluoro, chloro, bromo, methoxy, cyano, andmono-, di-, and trifluoromethyl, or R8 forms a ring system together withR10, as described herein,

R9 is hydrogen or fluoro, preferably hydrogen,

or R9 forms together with R8 or R10 and the ring to which they areattached a bicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoxadiazole, 1,3-benzodioxole, or2,2-difluoro-1,3-benzodioxole,

or R9 forms together with R10 and the ring to which they are attached abicyclic ring system selected from 3-oxo-2,3-dihydro-1H-isoindol,3-oxo-1,3-dihydro-2-benzofuran, and1-methyl-3-oxo-1,3-dihydro-2-benzofuran,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl,ethyl, propyl, ethenyl, propenyl, ethynyl, propargyl, methoxy, ethoxy,propyloxy, cyano, cyanomethyl, cyanoethyl, cyanomethoxy,fluoro(C₁₋₃)alkyl including trifluoromethyl, fluorinated and/orhydroxylated C₁₋₃alkoxy preferably fluoro(C₁₋₂)alkoxy, unsubstituted orfluorinated and/or hydroxylated C₁₋₂alkoxy(C₁₋₃)alkyl preferablymethoxypropyl, ethoxyethyl, and fluoromethoxymethyl, unsubstituted orfluorinated and/or hydroxylated C₁₋₂alkoxy(C₁₋₃) alkoxy preferablyfluoromethoxyethoxy, unsubstituted or fluorinated and/or hydroxylatedC₁₋₂alkoxy(C₂₋₃)alkenyl preferably methoxypropenyl and ethoxyethenyl,C₁₋₂alkoxycyclopropyl, C₁₋₂alkoxycarbonylcyclopropyl,cyclopropyl(C₁₋₂)alkoxy, acetyl, azido, and pentafluorosulfanyl, or R10forms a ring system together with R9, as described herein, and wherein,in a preferred embodiment, R8 and R10 are not both hydrogen,

R11 is selected from hydrogen, fluoro, fluoromethyl, chloro, methoxy andfluoromethoxy,

R12, if present, is selected from hydrogen and fluoro, andpharmaceutically acceptable salts, solvates, isotopes and co-crystalsthereof,

wherein in one preferred embodiment, if R9 does not form a ring with R8,then R10 is different from hydrogen.

One embodiment relates to compounds of Formula I,

wherein

X1 is N or C(R7),

X2 is NH, S or O, preferably NH or O, preferably NH,

R4 is hydrogen,

R5 is selected from hydrogen, fluoro, chloro and bromo,

R6 is selected from fluoro, bromo,chloro, nitro, azido, cyano, methyl,fluoromethyl, ethyl, fluoroethyl, isopropyl, cyclopropyl,cyclopropylmethyl, cyclopropylmethoxy, methoxy, ethoxy, fluoromethoxy,fluoroethoxy, methylsulfinyl, methylsulfonyl, benzyloxy, thienyl, andand is preferably chloro,

R7 is selected from hydrogen, methoxy, fluoro, chloro, bromo, cyano,fluoromethoxy, fluoroethoxy, and mono-, di- and trifluoromethyl,

X3 is N or C(R12),

R8 is selected from hydrogen, fluoro, chloro, and methoxy,

R9 is hydrogen or fluoro, preferably hydrogen,

R10 is selected from fluoro, chloro, bromo, cyano, cyanomethyl,cyanoethyl, cyanomethoxy, azido, methyl, ethyl, propyl, ethenyl,propenyl, ethynyl, propargyl, mono-, di-, and trifluoromethyl,cyclopropylmethoxy, cyclopropylethoxy, methoxycyclopropyl,ethoxycyclopropyl, methoxycarbonylcyclopropyl,ethoxycarbonylcyclopropyl, mono-, di- and trifluoromethoxy, mono-, di-,and trifluoroethoxy, ethoxymethyl, methoxyethyl, ethoxyethyl,methoxypropyl, fluoroethoxymethyl, fluoromethoxyethyl,fluoroethoxyethyl, fluoromethoxypropyl, ethoxymethoxy, methoxyethoxy,methoxypropoxy, fluoroethoxymethoxy, fluoromethoxyethoxy,fluoromethoxypropoxy, methoxyethenyl, methoxypropenyl,fluoromethoxyethenyl, fluoromethoxyethenyl, ethynyl, propargyl, andpentafluorosulfanyl,

R11 is selected from hydrogen, fluoro, chloro, fluoromethyl, methoxy,and fluoromethoxy,

R12, if present, is hydrogen or fluoro, preferably hydrogen

wherein, in a preferred embodiment, at least one of R8, and R11 isdifferent from hydrogen,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

One preferred embodiment relates to compounds of Formula I,

wherein

X1 is N, or C(R7),

X2 is NH, S or O, preferably NH,

R4 and R5 are both hydrogen,

R6 is methoxy, chloro or bromo, preferably chloro,

R7 is hydrogen, methoxy, fluoroor trifluoromethyl,

X3 is N or C(R12),

R9 forms together with R8 and the phenyl ring to which R8 and R9 areattached a 2,1,3-benzothiadiazole, a 1,3-benzodioxole, or a2,2-difluoro-1,3-benzodioxole,

R10 is hydrogen or fluoro,

R11 is selected from hydrogen, fluoro, cyano and methoxy, and ispreferably hydrogen,

R12, if present, is hydrogen or fluoro, preferably hydrogen, andpharmaceutically acceptable salts, solvates, isotopes and co-crystalsthereof.

One preferred embodiment relates to compounds of Formula I,

wherein

X1 is N or C(R7),

X2 is NH, S or O,

R4 and R5 are both hydrogen,

R6 is,selected from fluoro, chloro, bromo, cyano, azido, methyl, ethyl,isopropyl, fluoromethyl, cyclopropyl, methoxy, fluoromethoxy,methylsulfinyl, methylsulfonyl, thien-2-yl, thien-3-yl, and benzyloxyand is preferably chloro or bromo,

R7 is selected from hydrogen, methoxy, fluoro, chloro, bromo, cyano,mono-, di-, and trifluoromethyl, methylsulfinyl, methylsulfonyl, andfluoro(C₁₋₂)alkoxy,

X3 is N or C(R12),

R8 is selected from fluoro and methoxy,

R9 is hydrogen,

R10 is selected from fluoro, chloro, bromo, azido, cyano, cyanomethyl,cyanoethyl, cyanomethoxy, cyclopropyl(C₁₋₂)alkyl,cyclopropyl(C₁₋₂)alkoxy, C₁₋₂alkoxycyclopropyl,C₁₋₂alkoxycarbonylcyclopropyl, unsubstituted or fluorinated C₁₋₃ alkyl,preferably methyl, ethyl and fluoromethyl, unsubstituted or fluorinatedC₁₋₃ alkoxy, preferably methoxy, difluoromethoxy, difluoroethoxy andtrifluoroethoxy, unsubstituted or fluorinated C₂₋₃ alkenyl,unsubstituted or fluorinated C₂₋₃ alkynyl, unsubstituted or fluorinatedC₁₋₃ alkoxy(C₁₋₃)alkyl, preferably methoxypropyl, ethoxyethyl, andfluoromethoxymethyl, unsubstituted or fluorinated C₁₋₃alkoxy(C₁₋₃)alkoxy, preferably methoxyethoxy and fluoromethoxyethoxy,unsubstituted or fluorinated C₁₋₃ alkoxy(C₂₋₃)alkenyl, preferablymethoxypropenyl, ethoxyethenyl and fluoromethoxypropenyl, andpentafluorosulfanyl,

R11 is selected from hydrogen, fluoro and methoxy,

R12, if present, is hydrogen, and pharmaceutically acceptable salts,solvates, isotopes and co-crystals thereof.

A further embodiment relates to compounds of Formula I,

wherein

X1 is N or C(R7),

X2 is NH or O,

X3 is N or C(R12),

R4 and R5 are both hydrogen,

R6 is is selected from fluoro, chloro, bromo, iodo, cyano, azido,methyl, ethyl, isopropyl, trifluoromethyl, methylsulfinyl,methylsulfonyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy,methoxyethoxy, cyclopropylmethoxy, phenyl, benzyloxy, phenyloxy,thienyl, pyridyl, oxazole, thiazole, and isoxazole, or R6 forms togetherwith R7 and the carbon atoms to which R6 and R7 are attached, a ringselected from phenyl, pyridyl, and cyclopentyl,

R7 is selected from hydrogen, fluoro, chloro, bromo, iodo, methoxy,difluoromethoxy, trifluoromethoxy, methyl, difluoromethyl, andtrifluoromethyl, or R7 forms a ring together with R6 as describedherein,

R8 is selected from hydrogen, fluoro, chloro, bromo, iodo, methoxy,methyl, and trifluoromethyl, or R8 forms a ring system together withR10, as described herein,

R9 is selected from hydrogen, fluoro and chloro and is preferablyhydrogen,

or R9 forms together with R8 or R10 and the ring to which they areattached a bicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzooxadiazole, 2-oxo-2,3-dihydro-1,3-benzoxazole and1,3-benzodioxole, which is optionally substituted with two fluoros,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl,ethynyl, propargyl, fluoro(C₁₋₂)alkyl preferably trifluoromethyl,methoxy, fluoro(C₁₋₂)alkoxy, cyano, cyanomethyl, acetyl, azido,pentafluorosulfanyl, and methoxycarbonyl, or R10 forms a ring systemtogether with R9, as described herein,

R11 is selected from hydrogen, fluoro, chloro, bromo, and methoxy,

R12 is selected from hydrogen, fluoro, chloro, or bromo.

wherein, in a preferred embodiment, at least one of R8, R9, R10 and R11is different from hydrogen and unsubstituted alkyl,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

A further embodiment relates to compounds of Formula I,

wherein

X1 is N or C(R7),

X2 is NH or O,

X3 is N or C(R12),

R4 and R5 are both hydrogen,

R6 is selected from fluoro, chloro, bromo, azido, methyl, isopropyl,trifluoromethyl, methylsulfonyl, cyclopropyl, methoxy, phenyl,benzyloxy, thiophen-2-yl, and thiophen-3-yl, or R6 forms together withR7 and the carbon atoms to which R6 and R7 are attached, a ring selectedfrom phenyl, pyridyl, and cyclopentyl,

R7 is selected from hydrogen, fluoro, chloro, and methoxy, or R7 forms aring together with R6 as described herein,

R8 is selected from hydrogen, fluoro, chloro, bromo, methoxy, andtrifluoromethyl, or R8 forms a ring system together with R10, asdescribed herein,

R9 is hydrogen or fluoro, preferably hydrogen,

or R9 forms together with R8 or R10 and the ring to which they areattached a bicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzooxadiazole, 1,3-benzodioxole, or2,2-difluoro-1,3-benzodioxole,R10 is selected from hydrogen, fluoro,chloro, bromo, iodo, ethynyl, propargyl, methoxy, cyano, cyanomethyl,trifluoromethyl, fluoro(C₁₋₂)alkoxy, acetyl, azido, andpentafluorosulfanyl, or R10 forms a ring system together with R9, asdescribed herein, and wherein, in a preferred embodiment, R8 and R10 arenot both hydrogen,

R11 is selected from hydrogen, fluoro, chloro, and methoxy,

R12 is selected from hydrogen, and fluoro, and pharmaceuticallyacceptable salts, solvates, isotopes and co-crystals thereof.

One embodiment relates to compounds of Formula I,

wherein

X1 is N or C(R7),

X2 is NH or O, preferably NH,

R4 and R5 are both hydrogen,

R6 is bromo or chloro, preferably chloro,

R7 is hydrogen, methoxy, fluoro or trifluoromethyl,

X3 is N or C(R12),

R8 is selected from hydrogen, fluoro, chloro, and methoxy,

R9 is hydrogen of fluoro, preferably hydrogen,

R10 is selected from fluoro, chloro, bromo, cyano, cyanomethyl,trifluoromethyl, difluoroethoxy, trifluoroethoxy, andpentafluorosulfanyl,

R11 is selected from hydrogen, fluoro, chloro, and methoxy,

R12 is hydrogen or fluoro, preferably hydrogen,

wherein, in a preferred embodiment, at least one of R8, R9, R10 and R11is different from hydrogen,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

One preferred embodiment relates to compounds of Formula I,

wherein

X1 is N, or C(R7),

X2 is NH or 0, preferably NH,

R4 and R5 are both hydrogen,

R6 is chloro or bromo, preferably chloro,

R7 is hydrogen, methoxy, fluoro or trifluoromethyl,

X3 is N or C(R12),

R9 forms together with R8 and the phenyl ring to which R8 and R9 areattached a 2,1,3-benzothiadiazole or a 2,2-difluoro-1,3-benzodioxole,

R10 is hydrogen, or fluoro,

R11 is selected from hydrogen, fluoro and methoxy,

R12 is hydrogen or fluoro preferably hydrogen, and pharmaceuticallyacceptable salts, solvates, isotopes and co-crystals thereof.

One preferred embodiment relates to compounds of Formula I, wherein

X1 is N or C(R7),

X2 is NH,

R4 and R5 are both hydrogen,

R6 is chloro or bromo, preferably chloro,

R7 is hydrogen, methoxy, fluoro or trifluoromethyl,

X3 is N or C(R12),

R8 is selected from fluoro and methoxy,

R9 is hydrogen,

R10 is selected from fluoro, chloro, bromo, cyano, cyanomethyl,trifluoromethyl, difluoroethoxy, trifluoroethoxy, andpentafluorosulfanyl,

R11 is selected from hydrogen, fluoro and methoxy,

R12 is hydrogen, and pharmaceutically acceptable salts, solvates,isotopes and co-crystals thereof.

One embodiment of the present invention relates to compounds of thegeneral Formula I-2,

wherein

R2 is selected from hydrogen, fluoro, chloro, bromo, iodo and methoxy,preferably from hydrogen and fluoro, and wherein R4, R5, R6, R7 ifpresent, R8, R9, R10, R11, X1, X2, and X3 are as described for thecompounds of Formula I herein.

One embodiment relates to compounds of Formula I-2,

wherein

X1 is N or C(R7),

X2 is NH, S or O, preferably NH or O, more preferably NH,

R2 is hydrogen or fluoro,

R4 is hydrogen or fluoro,

R5 is selected from hydrogen and halogen,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido,nitro, unsubstituted or fluorinated C₁₋₃alkyl, unsubstituted orfluorinated C₁₋₃alkoxy, methylsulfinyl, methylsulfonyl, cyclopropyl,cyclopropylmethyl, cyclopropylmethoxy, benzyloxy, benzylsulfinyl,thienyl and pyridyl, and is preferably chloro or bromo,

R7 is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl,methoxy, fluoromethyl, fluoromethoxy, methylsulfinyl and methylsulfonyl,

X3 is N or C(R12),

R8 is selected from hydrogen, fluoro, chloro, cyano, methoxy andfluoromethoxy,

R9 is hydrogen or fluoro, preferably hydrogen,

R10 is selected from fluoro, chloro, bromo, iodo, azido, cyano,oxetanyl, cyano(C₁₋₂)alkyl, cyano(C₁₋₂)alkoxy, cyclopropyl(C₁₋₂)alkyl,cyclobutyl(C₁₋₂)alkyl, cyclopropyl(C₁₋₂)alkoxy, optionally fluorinatedC₁₋₂alkoxycyclopropyl, optionally fluorinatedC₁₋₂alkoxycarbonylcyclopropyl, unsubstituted or fluorinated C₁₋₃ alkyl,preferably methyl, ethyl and fluoromethyl, unsubstituted or fluorinatedC₁₋₃ alkoxy, preferably methoxy, difluoromethoxy, difluoroethoxy andtrifluoroethoxy, unsubstituted or fluorinated C₂₋₃ alkenyl,unsubstituted or fluorinated C₂₋₃ alkynyl, unsubstituted or fluorinatedC₁₋₃ alkoxy(C₁₋₃)alkyl, preferably methoxypropyl, ethoxyethyl, andfluoromethoxymethyl, unsubstituted or fluorinated C₁₋₃alkoxy(C₁₋₃)alkoxy, preferably methoxyethoxy and fluoromethoxyethoxy,unsubstituted or fluorinated C₁₋₃alkoxy(C₁₋₃)alkenyl, preferablymethoxypropenyl, ethoxyethenyl and fluoromethoxypropenyl, andpentafluorosulfanyl,

R11 is selected from hydrogen, fluoro, chloro, methoxy, fluoromethoxyand fluoromethyl.

R12, if present, is hydrogen or fluoro, preferably hydrogen wherein, ina preferred embodiment, at least one of R8 and R11 is different fromhydrogen,

wherein, in another preferred embodiment, R6 is not hydrogen, andpharmaceutically acceptable salts, solvates, isotopes and co-crystalsthereof.

One preferred embodiment relates to compounds of Formula I-2,

wherein

X1 is N, or C(R7),

X2 is NH, S or O, preferably NH,

R2 is hydrogen,

R4 is selected from hydrogen and fluoro,

R5 is selected from hydrogen, fluoro, chloro, and bromo,

R6 is selected from halogen, azido, cyano, benzyloxy, thienyl preferablythien-2-yl, unsubstituted or fluorinated C₁₋₃ alkyl preferably isopropyland fluoromethyl, cyclopropyl, cyclopropylmethyl, cyclopropylmethoxy,unsubstituted or fluorinated C₁₋₃alkoxy preferably methoxy,fluoromethoxy and fluoroethoxy, methylsulfinyl and methylsulfonyl,wherein R6 is preferably chloro or bromo,

R7 is selected from hydrogen, fluoro, bromo, chloro, cyano, methyl,fluoromethyl, methoxy, fluoromethoxy, fluoroethoxy, methylsulfinyl andmethylsulfonyl,

X3 is N or C(R12),

R8 is selected from hydrogen, fluoro, methoxy and fluoromethoxy, and ispreferably fluoro or methoxy,

R9 selected from hydrogen, fluoro and methoxy and is preferablyhydrogen,

R10 is selected from fluoro, chloro, bromo, iodo, cyano, azido, nitro,pentafluorosulfanyl, C₁₋₃alkyl, C₁₋₃alkoxy, C₂₋₃alkenyl, C₂₋₃alkynyl,cyclopropyl, cyclopropylmethoxy and cyclopropylethoxy, wherein eachalkyl, alkenyl and alkoxy group in R10 can be substituted with one ormore residues selected from fluoro, chloro, cyano, C₁₋₃alkyloxy andfluoro(C₁₋₃) alkyloxy, and wherein each cycloalkyl may be unsubstitutedor substituted with a residue selected from fluoro, methyl, C₁₋₂ alkoxy,C₁₋₂ alkoxycarbonyl and cyano,

R11 is selected from hydrogen, fluoro, methyl, fluoromethyl, methoxy,and fluoromethoxy,

R12, if present, is hydrogen or fluoro, preferably hydrogen,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof,

wherein in a preferred embodiment, if X1 is N, then X2 is also N, and

wherein in another preferred embodiment, at least one of R8 and R11 isdifferent from hydrogen.

One preferred embodiment relates to compounds of Formula I-2, wherein

X1 is N or C(R7),

X2 is NH,

R2, R4 and R5 are all hydrogen,

R6 is selected from fluoro, chloro, bromo, azido, isopropyl,cyclopropyl, methoxy, fluoromethyl, fluormethoxy, methylsulfonyl,methylsulfinyl and benzyloxy and is preferably chloro or bromo,

R7 is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl,ethyl, fluoromethyl, fluoroethyl, methoxy, fluoromethoxy, fluoroethoxy,methylsulfinyl and methylsulfonyl,

X3 is N or C(R12),

R8 is selected from fluoro and methoxy,

R9 is hydrogen,

R10 is selected from fluoro, chloro, bromo, iodo, cyano, azido,cyanomethyl, cyanoethyl, cyanomethoxy, cyanoethoxy, methyl, ethyl,propyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, methoxymethyl,methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, methoxy, ethoxy,propoxy, cyclopropylmethoxy, cyclopropylethoxy, methoxymethoxy,methoxyethoxy, methoxypropoxy, ethoxymethoxy, ethoxyethoxy,propoxymethoxy, ethenyl, propenyl, methoxyethenyl, methoxypropenyl,ethynyl, propynyl, methoxycarbonylethyl, ethoxycarbonylethyl,methoxycarbonylethenyl, ethoxycarbonylethenyl, and pentafluorosulfanyl,wherein each alkyl or alkoxy group in R10 can be fluorinated and/orhydroxylated, preferably fluorinated, one or more times, and whereineach cyclopropyl group may be substituted with a substituent selectedfrom fluoro, C₁₋₂ alkoxy and C₁₋₂ alkoxycarbonyl,

R11 is selected from hydrogen, fluoro, chloro, fluoromethyl, methoxy andfluoromethoxy,

R12, if present, is hydrogen or fluoro, and pharmaceutically acceptablesalts, solvates, isotopes and co-crystals thereof.

One embodiment relates to compounds of Formula I or I-2, wherein

X1 is N or C(R7),

X2 is NH, S or O and is preferably NH,

X3 is N or CR12,

R2, if present, R4, R5 and R9 are all hydrogen,

R6 is selected from halogen, cyano, C₁₋₃alkoxy, C₁₋₃alkyl,C₁₋₆cycloalkyl preferably C₃₋₄cycloalkyl, C₃₋₆cycloalkyloxy preferablyC₃₋₄cycloalkyloxy, C₃₋₆heterocycloalkyl preferably C₃₋₄heterocycloalkyl,and C₃₋₆heterocycloalkyloxy preferably C₃₋₄heterocycloalkyloxy, each ofwhich can be optionally substituted with a residue selected from fluoroand unsubstituted or fluorinated C₁₋₃alkoxy,

R7 is selected from hydrogen, halogen, cyano, C₁₋₃alkoxy, C₁₋₃alkyl,C₃₋₆cycloalkyl preferably C₃₋₄cycloalkyl, C₃₋₆cycloalkyloxy preferablyC₃₋₄cycloalkyloxy, C₃₋₆heterocycloalkyl preferably C₃₋₄heterocycloalkyl,and C₃₋₆heterocycloalkyloxy preferably C₃₋₄heterocycloalkyloxy, each ofwhich can be optionally substituted with a residue selected from fluoroand unsubstituted or fluorinated C₁₋₃alkoxy,

R8 is selected from fluoro, methoxy and fluoromethoxy, preferably fromfluoro and methoxy,

R10 is selected from halogen, C₁₋₄aalkoxy, C₁₋₄aalkyl, C₂₋₃alkenylC₂₋₃alkynyl, C₃₋₆cycloalkyl preferably C₃₋₄cycloalkyl, C₃₋₆cycloalkyloxypreferably C₃₋₄cycloalkyloxy, C₃₋₆heterocycloalkyl preferablyC₃₋₄heterocycloalkyl, and C₃₋₆heterocycloalkyloxy preferablyC₃₋₄heterocycloalkyloxy, each of which can be optionally substitutedwith a residue selected from fluoro, cyano and unsubstituted orfluorinated C₁₋₃alkoxy,

R11 is selected from hydrogen, fluoro, methoxy and fluoromethoxy,preferably from fluoro and methoxy,

and R12, if present is selected from hydrogen, fluoro, fluoromethyl,methoxy and fluoromethoxy.

One embodiment of the present invention relates to compounds of FormulaI, wherein X1 is CR7 and X2 is NH, thus having the structure of FormulaII

wherein R4, R5, R6, R7, R8, R9, R10, R11, R12, if present, and X3 are asdescribed as for Formula I herein and pharmaceutically acceptable salts,solvates, isotopes and co-crystals thereof.

Another embodiment relates to compounds of Formula I, wherein X1 is Nand X2 is NH, thus having the structure of Formula III

wherein R4, R5, R6, R8, R9, R10, R11, R12, if present, and X3 are asdescribed as for

Formula I herein and pharmaceutically acceptable salts, solvates,isotopes and co-crystals thereof.

Another embodiment relates to compounds of Formula I, wherein X2 is Oand X1 is C(R7), thus having the structure of Formula IV

wherein R4, R5, R6, R7, R8, R9, R10, R11, R12, if present, and X3 are asdescribed as for Formula I herein and pharmaceutically acceptable salts,solvates, isotopes and co-crystals thereof.

Another embodiment relates to compounds of Formula I, wherein X2 is Sand X1 is C(R7), thus having the structure of Formula V

wherein R4, R5, R6, R7, R8, R9, R10, R11, R12, if present, and X3 are asdescribed as for Formula I herein and pharmaceutically acceptable salts,solvates, isotopes and co-crystals thereof.

It is to be understood that subsequently in any definition of thesubstituents of compounds of Formula II, Ill, IV and V, the potentialreference to R7 only applies to compounds of Formula II, IV and V,whereas the other substitutions apply to compounds of Formula III aswell.

In one embodiment of the compounds of Formula I, II, Ill, IV and V, X3is C(R12).

In one embodiment of the compounds of Formula I, II, Ill IV and V, X3 isN.

In one embodiment, in the compounds having Formula III, at least one ofR4, R5 and R6 is different from hydrogen, in particular at least one ofR5 and R6 is different from hydrogen.

In one embodiment, in the compounds of Formula III, if R6 is hydrogen,then R5 is halogen; in one particular embodiment, R5 is iodo.

In one embodiment, in the compounds of Formula I, II, IV and/or V, atleast one of R5, R6 and R7 is different from hydrogen.

In one embodiment, in the compounds of Formula I, II, Ill, IV and/or V,if R6 is hydrogen, then R7 is different from hydrogen, and is preferablyselected from fluoro, chloro, bromo, cyano, methoxy, unsubstituted orfluorinated C₁₋₂alkyl, unsubstituted or fluorinated C₁₋₂ alkoxy,unsubstituted or fluorinated methylsulfonyl, and unsubstituted orfluorinated methylsulfinyl, and is preferably selected from fluoro,chloro, bromo, methyl, methoxy, fluoromethyl, fluoromethoxy,fluoroethoxy, methylsulfonyl and methylsulfinyl.

In one preferred embodiment, in the compounds of Formula I, II, Ill, IVand V, if R10 is hydrogen, then R8 and R11 are both different fromhydrogen.

A further embodiment relates to compounds of Formula II, Ill, IV or V,

wherein

X3 is N or C(R12),

R4 is hydrogen,

R5 is selected from hydrogen, fluoro, chloro and bromo,

R6 is selected from fluoro, chloro, bromo, iodo, cyano, azido, nitro,methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methylsulfinyl,methylsulfonyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy,methoxymethoxy, methoxyethoxy, ethoxymethoxy, cyclopropylmethoxy,phenyl, benzyloxy, phenyloxy, benzylsulfinyl, benzylsulfonyl, thienyl,pyridyl, oxazole, thiazole, and isoxazole, wherein wherein each alkyland alkoxy group in R6 can be substituted with one or more residuesselected from fluoro, cyano, and hydroxy and wherein each phenyl,thienyl, pyridyl, oxazol, thiazole and isoxazol can be optionallysubstituted one or more times, preferably with a substitution selectedfrom halogen, methoxy, fluoromethoxy, methyl and fluoromethyl, or, inthe compounds of Formula II, IV or V, in particular in the compounds offormula II, R6 may form together with R7 and the carbon atoms to whichR6 and R7 are attached, a ring selected from phenyl, pyridyl,cycloxhexyl and cyclopentyl, each of which can be unsubstituted orsubstituted one or more times with a group selected from methyl,fluorinated methyl, methoxy, fluorinated methoxy, hydroxy, chloro andfluoro,

R7 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano,methoxy, ethoxy, methylsulfinyl, methylsulfonyl, methyl, ethyl,fluoromethyl, fluoroethyl, and fluoro(C₁₋₂)alkoxy, or R7 forms a ringtogether with R6 as described herein,

R8 is selected from hydrogen, fluoro, chloro, bromo, iodo, methoxy,fluoromethyl and fluoromethoxy, or R8 forms a ring system together withR10, as described herein,

R9 is selected from hydrogen, methyl, methoxy, fluoro and chloro and ispreferably hydrogen, or R9 forms together with R8 or R10 and the ring towhich they are attached a bicyclic ring system selected from2,1,3-benzothiadiazole, 2,1,3-benzoxadiazole,2-oxo-2,3-dihydro-1,3-benzoxazole and 1,3-benzodioxole, which isoptionally substituted with two fluoros, or R9 forms together with R10and the ring to which they are attached a bicyclic ring system selectedfrom 3-oxo-2,3-dihydro-1H-isoindol,1,1-dioxo-2,3-dihydro-1-benzothiophene, 3-oxo-1,3-dihydro-2-benzofuranwhich can be optionally methylated in 1 position,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo,unsubstituted or fluorinated C₁₋₃alkenyl including ethenyl and propenyl,unsubstituted or fluorinated C₁₋₃alkynyl including ethynyl andpropargyl, unsubstituted or fluorinated and/or hydroxylated C₁₋₃alkylincluding methyl, ethyl, isopropyl and trifluoromethyl, unsubstituted orfluorinated and/or hydroxylated C₁₋₃alkoxy including methoxy andfluoro(C₁₋₂)alkoxy, cyano, cyanomethyl, cyanomethoxy, cyclopropyl,cyclopropylmethoxy, cyclopropylethoxy, acetyl, azido, nitro,pentafluorosulfanyl, unsubstituted or fluorinated and/or hydroxylatedC₁₋₃alkoxy(C₁₋₃)alkyl, preferably methoxypropyl and ethoxyethyl,unsubstituted or fluorinated and/or hydroxylated C₁₋₃alkoxy(C₁₋₃)alkoxy,preferably methoxyethoxy and fluoromethoxyethoxy, unsubstituted orfluorinated and/or hydroxylated C₁₋₃alkoxy(C₂₋₃)alkenyl, preferablymethoxypropenyl and ethoxyethenyl, unsubstituted or fluorinated and/orhydroxylated C₁₋₃alkoxy(C₂₋₃)alkynyl, unsubstituted or fluorinatedand/or hydroxylated C₁₋₃alkoxycarbonyl(C₁₋₃)alkyl preferablyethoxycarbonylethyl, and unsubstituted or fluorinated and/orhydroxylated C₁₋₃alkoxycarbonyl(C₁₋₃)alkenyl preferablyethoxycarbonylethenyl, wherein each cyclopropyl group in R10 may beunsubstituted or further substituted with one or more substituentsselected from fluoro, chloro, cyano, optionally fluorinated C₁₋₂alkoxyand optionally fluorinated C₁₋₂alkoxycarbonylor R10 forms a ring systemtogether with R9, as described herein,

R11 is selected from hydrogen, fluoro, chloro, bromo, unsubstituted orfluorinated methyl, and unsubstituted or fluorinated methoxy,

R12, if present, is selected from hydrogen, fluoro, chloro, or bromo,and is preferably hydrogen or fluoro;

wherein, in a preferred embodiment, at least one, preferably two of R8,R10 and R11, are different from hydrogen and unsubstituted alkyl, andwherein in one embodiment the residues in R10 are preferablyunsubstituted or fluorinated, and pharmaceutically acceptable salts,solvates, isotopes and co-crystals thereof.

One embodiment relates to compounds of Formula II, Ill IV and V, wherein

X3 is N or C(R12),

R4 is hydrogen,

R5 is selected from hydrogen, fluoro, chloro and bromo, R6 is selectedfrom fluoro, chloro, bromo, azido, cyano, methyl, ethyl, n-propyl,isopropyl, trifluoromethyl, methylsulfinyl, methylsulfonyl, cyclopropyl,methoxy, phenyl, benzyloxy, thiophen-2-yl, and thiophen-3-yl, whereineach alkyl and alkoxy group in R6 can be unsubstituted or substitutedwith one or more residues selected from fluoro, cyclopropyl and methoxy,preferably with fluoro,

R7 is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl,ethyl, methylsulfinyl, methylsulfonyl, fluoromethyl, fluoroethyl,methoxy, fluoromethoxy, fluoroethoxy, and fluoropropoxy,

R8 is selected from hydrogen, fluoro, chloro, bromo, methoxy,fluoromethyl and fluoromethoxy, or R8 forms a ring system together withR10, as described herein,

R9 is hydrogen or fluoro, preferably hydrogen, or R9 forms together withR8 or R10 and the ring to which they are attached a bicyclic ring systemselected from 2,1,3-benzothiadiazole, 2,1,3-benzoxadiazole,2-oxo-2,3-dihydro-1,3-benzoxazole, 1,3-benzodioxole, or2,2-difluoro-1,3-benzodioxole, or R9 forms together with R10 and thering to which they are attached a bicyclic ring system selected from3-oxo-2,3-dihydro-1H-isoindol, 1,1-dioxo-2,3-dihydro-1-benzothiophene,3-oxo-1, 3-dihydro-2-benzofu ran and 1-methyl-3-oxo-1,3-dihydro-2-benzofuran,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl,ethyl, propyl, ethenyl, propenyl, ethynyl, propargyl, fluoro(C₁₋₃) alkylpreferably trifluoromethyl, methoxy, ethoxy, fluoro(C₁₋₃)alkoxy, cyano,cyanomethyl, cyanoethyl, cyanomethoxy, acetyl, azido, unsubstituted orfluorinated C₁₋₃alkoxy(C₁₋₃)alkyl, unsubstituted or fluorinated C₁₋₃alkoxy(C₁₋₃)alkoxy, unsubstituted or fluorinatedC₁₋₃alkoxy(C₂₋₃)alkenyl, unsubstituted or fluorinatedC₁₋₃alkoxy(C₂₋₃)alkynyl, unsubstituted or fluorinatedC₁₋₃alkoxycyclopropyl, unsubstituted or fluorinated C₁₋₃alkoxycarbonylcyclopropyl, and pentafluorosulfanyl, or R10 forms a ringsystem together with R9, as described herein, and wherein, in apreferred embodiment, R8 and R10 are not both hydrogen,

R11 is selected from hydrogen, fluoro, chloro, fluorinated methyl, andunsubstituted or fluorinated methoxy,

R12, if present, is selected from hydrogen and fluoro, andpharmaceutically acceptable salts, solvates, isotopes and co-crystalsthereof.

A further embodiment relates to compounds of Formula II, Ill or IV,

wherein

X3 is N or C(R12),

R4 and R5 are both hydrogen,

R6 is is selected from fluoro, chloro, bromo, iodo, cyano, azido,methyl, ethyl, isopropyl, trifluoromethyl, acetyl, methylsulfinyl,methylsulfonyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy,methoxyethoxy, cyclopropylmethoxy, phenyl, benzyloxy, phenyloxy,thienyl, pyridyl, oxazole, thiazole, and isoxazole,

or R6 forms together with R7 and the carbon atoms to which R6 and R7 areattached, a ring selected from phenyl, pyridyl, and cyclopentyl,R7 isselected from hydrogen, fluoro, chloro, bromo, iodo, methoxy, ethoxy,methyl, trifluoromethyl and fluoro(C₁₋₂)alkoxy, or R7 forms a ringtogether with R6 as described herein,

R8 is selected from hydrogen, fluoro, chloro, bromo, iodo, methoxy,methyl, and trifluoromethyl, or R8 forms a ring system together withR10, as described herein,

R9 is selected from hydrogen, fluoro and chloro and is preferablyhydrogen,

or R9 forms together with R8 or R10 and the ring to which they areattached a bicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzooxadiazole, 2-oxo-2,3-dihydro-1,3-benzoxazole and1,3-benzodioxole, which is optionally substituted with two fluoros, R10is selected from hydrogen, fluoro, chloro, bromo, iodo, ethynyl,propargyl, trifluoromethyl, methoxy, fluoro(C₁₋₂)alkoxy, cyano,cyanomethyl, acetyl, azido, pentafluorosulfanyl, and methoxycarbonyl, orR10 forms a ring system together with R9, as described herein,

R11 is selected from hydrogen, fluoro, chloro, bromo, and methoxy,

R12 is selected from hydrogen, fluoro, chloro, or bromo.

wherein, in a preferred embodiment, at least one of R8, R9, R10 and R11is different from hydrogen and unsubstituted alkyl,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

One embodiment relates to compounds of Formula II, Ill and IV, wherein

X3 is N or C(R12),

R4 and R5 are both hydrogen,

R6 is selected from fluoro, chloro, bromo, azido, methyl, isopropyl,trifluoromethyl, methylsulfonyl, cyclopropyl, methoxy, phenyl,benzyloxy, thiophen-2-yl, and thiophen-3-yl,

R7 is selected from hydrogen, fluoro, chloro, and methoxy,

R8 is selected from hydrogen, fluoro, chloro, bromo, methoxy, andtrifluoromethyl, or R8 forms a ring system together with R10, asdescribed herein,

R9 is hydrogen or fluoro, preferably hydrogen,

or R9 forms together with R8 or R10 and the ring to which they areattached a bicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzooxadiazole, 2-oxo-2,3-dihydro-1,3-benzoxazole,1,3-benzodioxole, or 2,2-difluoro-1,3-benzodioxole,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl,ethynyl, trifluoromethyl, methoxy, fluoro(C₁₋₂)alkoxy, cyano,cyanomethyl, acetyl, azido, and pentafluorosulfanyl, or R10 forms a ringsystem together with R9, as described herein, and wherein, in apreferred embodiment, R8 and R10 are not both hydrogen,

R11 is selected from hydrogen, fluoro, chloro, and methoxy,

R12 is selected from hydrogen, and fluoro, and pharmaceuticallyacceptable salts, solvates, isotopes and co-crystals thereof.

One embodiment relates to compounds of Formula II, Ill IV or V, wherein

R4 and R5 are both hydrogen,

R6 is methoxy, trifluoromethyl, bromo or chloro, preferably chloro,

R7 is hydrogen, fluoro, methoxy, or trifluoromethyl,

X3 is C(R12),

R9 forms together with R8 or R10 and the phenyl ring to which R8 and R9,or R9 and R10 are attached, a 2,1,3-benzothiadiazole or2,2-difluoro-1,3-benzodioxole,

R10 is selected from hydrogen and fluoro, R11 is selected from hydrogen,fluoro and methoxy, and is preferably hydrogen, and R12, if present, ishydrogen or fluoro, and pharmaceutically acceptable salts, solvates,isotopes and co-crystals thereof.

One embodiment relates to compounds of Formula II, Ill or IV,

wherein

R4 and R5 are both hydrogen,

R6 is bromo or chloro, preferably chloro,

R7 is hydrogen, fluoro, methoxy, or trifluoromethyl,

X3 is C(R12),

R9 forms together with R8 or R10 and the phenyl ring to which R8 and R9,or R9 and R10 are attached, a 2,1,3-benzothiadiazole or2,2-difluoro-1,3-benzodioxole,

R10 is selected from hydrogen and fluoro,

R11 is selected from hydrogen, fluoro and methoxy, and

R12 is hydrogen, and pharmaceutically acceptable salts, solvates,isotopes and co-crystals thereof.

One preferred embodiment relates to compounds of Formula I,

wherein

R 4 and R5 are both hydrogen,

R6 is chloro or bromo, preferably chloro,

R7 is hydrogen, fluoro, methoxy, or trifluoromethyl,

X3 is N or C(R12),

R8 is selected from fluoro, chloro and methoxy,

R9 is hydrogen,

R10 is selected from fluoro, chloro, bromo, cyano, cyanomethyl,trifluoromethyl and pentafluorosulfanyl,

R11 is selected from hydrogen, fluoro and methoxy,

R12 is hydrogen and pharmaceutically acceptable salts, solvates,isotopes and co-crystals thereof.

One preferred embodiment of the present invention relates to compound ofFormula II, Ill IV or V, wherein

X3 is N or C(R12),

R4 is hydrogen or fluoro, preferably hydrogen,

R5 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl,methoxy, and fluorinated C₁₋₂ alkyl, including trifluoromethyl,preferably hydrogen, methyl, fluoro, chloro, bromo or iodo, or R5 formsa ring together with R6 as described herein,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido,unsubstituted or substituted C₁₋₃ alkyl, preferably methyl, ethyl,isopropyl, difluoromethyl, difluoroethyl, trifluoroethyland/trifluoromethyl, unsubstituted or substituted C₂₋₃ alkenyl,unsubstituted or substituted C₂₋₃ alkynyl, unsubstituted orunsubstituted or substituted (C₁₋₃)alkylsulfinyl preferablymethylsulfinyl, unsubstituted or unsubstituted or substituted C₁₋₃alkylsulfonyl preferably methylsulfonyl, unsubstituted or substitutedC₃₋₆ cycloalkyl preferably cyclopropyl, unsubstituted or substitutedC₃₋₆ cycloalkyl(C₁₋₃)alkyl preferably cyclopropylmethyl, unsubstitutedor substituted C₃₋₆ cycloalkyl(C₁₋₃)alkyloxy preferablycyclopropylmethoxy, unsubstituted or substituted C₃₋₆ heterocycloalkyl,unsubstituted or substituted C₃₋₆ heterocycloalkyl(C₁₋₃)alkyloxypreferably heterocyclopropylmethoxy unsubstituted or substituted C₃₋₆cycloalkoxy, unsubstituted or substituted C₃₋₆ heterocycloalkoxy,unsubstituted or substituted C₁₋₃ alkoxy preferably methoxy,difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxyunsubstituted or substituted C₁₋₃alkoxy(C₁₋₃)alkoxy, preferablymethoxyethoxy, unsubstituted or substituted C₁₋₃alkoxy(C₁₋₃)alkyl, C₃₋₆cycloalkyl(C₁₋₃)alkoxy preferably cyclopropylmethoxy, unsubstituted orsubstituted phenyl, unsubstituted or substituted phenyl(C₁₋₃)alkylpreferably benzyl, unsubstituted or substituted phenyl(C₁₋₃)alkoxypreferably benzyloxy, unsubstituted or substituted phenyloxy,unsubstituted or substituted phenyl(C₁₋₃)alkylsulfonyl preferablybenzylsulfonyl, unsubstituted or substituted phenyl(C₁₋₃)alkylsulfinylpreferably benzylsulfinyl, unsubstituted or substituted thienyl,unsubstituted or substituted pyridyl, unsubstituted or substitutedoxazole, unsubstituted or substituted thiazole, and unsubstituted orsubstituted isoxazole, and wherein each optional substitution in R6 ispreferably selected from fluoro, chloro, unsubstituted or fluorinatedmethyl, unsubstituted or fluorinated methoxy, hydroxy, and cyano,provided that in the compounds of Formula III, if R6 is hydrogen, thenat least one of R5 and R7 is different from hydrogen, wherein R5 ispreferably iodo, or

-   -   (i) R6 forms together with R7 and the carbon atoms to which R6        and R7 are attached, an unsubstituted or substituted phenyl, an        unsubstituted or substituted pyridyl, an unsubstituted or        substituted cyclopentyl or an unsubstituted or substituted        cyclohexyl,        -   wherein each substitution, if present, is selected from            halogen, hydroxy, methyl or methoxy, wherein each methyl or            methoxy can be unsubstituted or substituted with one or more            substituents selected from halogen, preferably fluoro, and            methoxy,    -   or    -   (ii) R6 forms together with R5 and the carbon atoms to which R6        and R5 are attached, a 1,3-dioxolane which may be unsubstituted        or substituted with one or two substituents selected from fluoro        and methyl,

R7 is selected hydrogen, fluoro, chloro, bromo, iodo, cyano, C₁₋₃ alkyl,C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃)alkyl preferablydifluoromethyl or trifluoromethyl, fluoro(C₁₋₃)alkoxy preferablydifluoromethoxy, difluoroethoxy, trifluoroethoxy and trifluoromethoxy,methylsulfinyl, methylsulfonyl, fluorinated methylsulfinyl, fluorinatedmethylsulfonyl, substituted or unsubstituted C₃₋₆ cycloalkyl,substituted or unsubstituted C₃₋₆ heterocycoalkyl, substituted orunsubstituted C₃₋₆ cycloalkyloxy, substituted or unsubstituted C₃₋ ₆heterocycoalkyloxy, substituted or unsubstituted C₅-₆ heteroaryl,substituted or unsubstituted C₅₋₆ heteroaryloxy, and C₅₋₆heteroarylmethoxy, wherein the heteroaryl is preferably selected frompyridyl, oxazol and isoxazol, and wherein the heteroaryl may besubstituted with one or more substituents selected from halogen,unsubstituted or fluorinated methyl, unsubstituted or fluorinatedmethoxy, or R7 forms a ring together with R6 as described herein,

R8 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃)alkoxy, C₁₋₃alkyl preferablymethyl, and fluoro(C₁₋₃)alkyl preferably trifluoromethyl,

R9 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃)alkoxy, C₁₋₃alkyl preferablymethyl, and fluoro(C₁₋₃)alkyl preferably trifluoromethyl, and ispreferably hydrogen, methoxy, or fluoro,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkyl,halo(C₁₋₃)alkyl, preferably fluoro(C₁₋₃)alkyl preferablytrifluoromethyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkyloxy,halo(C₁₋₃)alkyloxy preferably fluoro(C₁₋₃)alkoxy, cyano, cyanomethyl,cyanoethyl, unsubstituted or fluorinated C₁₋₃alkylcarbonyl preferablyacetyl, unsubstituted or fluorinated C₁₋₃ alkoxycarbonyl preferablymethoxycarbonyl, cyclopropyl, cyclopropyloxy, azido,pentafluorosulfanyl, and nitro, wherein any cyclopropyl residue ispreferably substituted with a group selected from fluoro, cyano,C₁₋₃alkoxy and C₁₋₃alkoxycarbonyl, and wherein each alkyl, alkoxy,alkenyl or alkynyl in R10 can be optionally further substituted with oneor more substituents selected from cyclopropyl, fluoro, chloro, bromo,iodo, cyano, hydroxy, halo(C₁₋₃)alkoxy and C₁₋₃ alkoxy, preferably withfluoro, methoxy, fluoromethoxy or fluoroethoxy,

R11 is selected from hydrogen, fluoro, chloro, cyano, C₁₋₃ alkylpreferably methyl, fluoro(C₁₋₃)alkyl preferably fluoromethyl, C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃)alkoxy preferablyfluoro(C₁₋₂)alkoxy, and is more preferably hydrogen, fluoro, chloro,methoxy, fluoromethoxy or fluoromethyl,

R12, if present, is selected from hydrogen, fluoro, chloro, bromo, iodo,C₁₋₃ alkyloxy preferably methoxy, fluoro(C₁₋₃)alkoxy preferablyfluoro(C₁₋₂)alkoxy, C₁₋₃ alkyl preferably methyl, and fluoro(C₁₋₃)alkylpreferably trifluoromethyl, and is more preferably hydrogen, fluoro, orfluoromethyl,

wherein, in a preferred embodiment, at least one of R8, R10 and R11 isdifferent from hydrogen, and more preferably at least one of R8, R10 andR11 is also different from unsubstituted alkyl,

and wherein, preferably, in the compounds of Formula II, at least one ofR5, R6 and R7, if present, is not hydrogen,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

One preferred embodiment of the present invention relates to compound ofFormula II, Ill or IV, wherein

X3 is N or C(R12),

R4 is hydrogen,

R5 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl,methoxy, acetyl, methoxycarbonyl and trifluoromethyl, preferablyhydrogen, methyl or iodo, or R5 forms a ring together with R6 asdescribed herein,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido,unsubstituted or substituted C₁₋₃ alkyl, preferably methyl, ethyl,isopropyl, or trifluoromethyl, unsubstituted or fluorinated C₁₋₂alkylcarbonyl, unsubstituted or fluorinated C₁₋₂ alkoxycarbonyl,(C₁₋₃)alkylsulfinyl preferably methylsulfinyl, C₁₋₃ alkylsulfonylpreferably methylsulfonyl, C₃₋₆ cycloalkyl preferably cyclopropyl, C₃₋₆cycloalkyl(C₁₋₃)alkyl preferably cyclopropylmethyl, C₃₋₆heterocycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆ heterocycloalkoxy,unsubstituted or substituted C₁₋₃ alkoxy preferably methoxy,unsubstituted or substituted C₁₋₃alkoxy(C₁₋₃)alkoxy, preferablymethoxyethoxy, C₃₋₆ cycloalkyl(C₁₋₃)alkoxy preferablycyclopropylmethoxy, unsubstituted or substituted phenyl, unsubstitutedor substituted phenyl(C₁₋₃)alkoxy preferably benzyloxy, unsubstituted orsubstituted phenyloxy, thienyl, pyridyl, oxazole, thiazole, andisoxazole, and wherein each optional substitution in R6 is preferablyselected from fluoro, chloro, methyl, methoxy, and cyano,

provided that in the compounds of Formula III, if R6 is hydrogen, thenR5 is different from hydrogen, and is preferably iodo,

or

-   -   (i) R6 forms together with R7 and the carbon atoms to which R6        and R7 are attached, an unsubstituted or substituted phenyl, an        unsubstituted or substituted pyridyl, an unsubstituted or        substituted cyclopentyl or an unsubstituted or substituted        cyclohexyl,    -   wherein each substitution, if present, is selected from halogen,        methyl or methoxy, wherein each methyl or methoxy can be        unsubstituted or substituted with one or more substituents        selected from fluoro and methoxy,    -   or    -   (ii) R6 forms together with R5 and the carbon atoms to which R6        and R5 are attached, a 1,3-dioxolane which may be unsubstituted        or substituted with one or two substituents selected from fluoro        and methyl,

R7 is selected hydrogen, fluoro, chloro, bromo, iodo, cyano, C₁₋₃ alkyl,C₁₋₃alkyloxy, fluoro(C₁₋₃)alkyl preferably trifluoromethyl,fluoro(C₁₋₃)alkoxy preferably trifluoromethoxy, unsubstituted orfluorinated C₁₋₂ alkylcarbonyl, unsubstituted or fluorinated C₁₋₂alkoxycarbonyl, methylsulfinyl, and methylsulfonyl, or R7 forms a ringtogether with R6 as described herein,

R8 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkyloxypreferably methoxy, fluoro(C₁₋₃)alkoxy, C₁₋₃ alkyl preferably methyl,and fluoro(C₁₋₃)alkyl preferably trifluoromethyl,

R9 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃)alkoxy, C₁₋₃ alkyl preferablymethyl, and fluoro(C₁₋₃)alkyl preferably trifluoromethyl, and ispreferably hydrogen fluoro, chloro, or bromo,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyl,halo(C₁₋₃)alkyl, preferably fluoro(C₁₋₃)alkyl, particularlytrifluoromethyl, C₂₋₃ alkynyl, C₁₋₃ alkyloxy, halo(C₁₋₃) alkyloxy,preferably fluoro(C₁₋₂)alkoxy, cyano, cyanomethyl, unsubstituted orfluorinated C₁₋₃ alkylcarbonyl preferably acetyl, unsubstituted orfluorinated C₁₋₃ alkoxycarbonyl preferably methoxycarbonyl, azido,pentafluorosulfanyl, and nitro,

R11 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkylpreferably methyl, fluoro(C₁₋₃)alkyl preferably trifluoromethyl, C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃) alkoxy, preferablyfluoro(C₁₋₂)alkoxy, unsubstituted or fluorinated C₁₋₃ alkylcarbonylpreferably acetyl, unsubstituted or fluorinated C₁₋₃ alkoxycarbonylpreferably methoxycarbonyl and cyano, and, and is more preferablyhydrogen, fluoro, chloro or bromo,

R12 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃)alkoxy preferablyfluoro(C₁₋₂)alkoxy, C₁₋₃ alkyl preferably methyl, and fluoro(C₁₋₃)alkylpreferably trifluoromethyl, and is more preferably hydrogen, fluoro,chloro, or bromo,

wherein, in a preferred embodiment, at least one of R8, R9, R10 and R11is different from hydrogen, and more preferably at least one of R8, R9,R10 and R11 is also different from unsubstituted alkyl,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof

One preferred embodiment of the present invention relates to compoundsof Formula II, Ill IV or V, wherein

R4 is hydrogen or fluoro, more preferably hydrogen,

R5 is selected from hydrogen, fluoro, bromo, chloro, iodo and methyl,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl,ethyl, propyl preferably isopropyl, acetyl, cyano, nitro, azido,methylsulfonyl, methylsulfinyl, fluoro(C₁₋₂)alkyl, methoxy, ethoxy,fluoro(C₁₋₂)alkoxy, C₁₋₂alkoxymethoxy, fluorinated (C₁₋₂)alkoxymethoxy,fluorinated (C₁₋₂)alkoxymethyl, phenyl, phenoxy, benzyloxy,benzylsulfinyl, pyrid-3-yl, thien-2-yl, thien-3-yl, cyclopropyl,cyclopropyloxy, cyclopropylmethyl, and cyclopropylmethoxy, wherein eachphenyl, thienyl, pyridyl, and cyclopropyl can be optionally substitutedone or more times with methoxy, fluoro and/or chloro, and wherein R6 ispreferably not hydrogen, or, in compounds of Formula II, R6 may form,together with R7 and the carbon atoms to which R6 and R7 are attached aring selected from an unsubstituted or substituted phenyl, unsubstitutedor substituted pyridyl, and unsubstituted or substituted cyclohexyl, andunsubstituted or substituted cyclopentyl, wherein any substitution ofsuch phenyl, pyridyl and cyclopentyl is selected from fluoro, chloro,hydroxy, fluorinated or unsubstituted methoxy and fluorinated orunsubstituted methyl, wherein the ring is preferably selected fromunsubstituted phenyl, pyridyl or cyclopentyl,

R7 is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl,methoxy, methylsulfonyl, methylsulfinyl, fluoromethyl, fluoroethyl,fluoromethoxy, fluoroethoxy, and optionally methylated isoxazol which ispreferably 3,5-dimethyl-1,2-oxazol,

X3 is N or C(R12), and is preferably C(R12),

R8 is selected from hydrogen, methoxy, fluoromethoxy, cyano, chloro andfluoro, and is preferably fluoro, methoxy or fluoromethoxy,

R9 is selected from hydrogen, methoxy, and fluoro,

R10 is selected from hydrogen, ethenyl, propenyl, ethynyl, propargyl,cyano, cyanomethyl, acetyl, fluoro, chloro, bromo, iodo, azido,nitro,unsubstituted or fluorinated C₁₋₃alkyl, preferably methyl andtrifluoromethyl, hydroxy(C₁₋₃)alkoxy preferably hydroxyethoxy,cyano(C₁₋₃)alkoxy preferably cyanomethoxy, cyclopropyl(C₁₋₂)alkyl,cyclopropyl(C₁₋₃)alkoxy preferably cyclopropylmethoxy, unsubstituted orfluorinated C₁₋₃alkoxy preferably difluoroethoxy and trifluoroethoxy,unsubstituted or fluorinated C₁₋₂alkoxy(C₁₋₃)alkyl preferablymethoxypropyl and ethoxyethyl, unsubstituted or fluorinatedC₁₋₂alkoxy(C₁₋₃)alkoxy preferably methoxyethoxy and fluoromethoxyethoxy,unsubstituted or fluorinated C₁₋₂alkoxy(C₂₋₃)alkenyl preferablymethoxypropenyl, unsubstituted or fluorinated C₁₋₂alkoxy (C₂₋₃)alkynyl,and pentafluorosulfanyl, C₁₋₂alkoxycyclopropyl andC₁₋₂alkoxycarbonylcyclopropyl,

R11 is selected from hydrogen, fluoro, chloro, cyano, fluoromethyl,methoxy and fluoromethoxy,

R12 is hydrogen or fluoro,

and wherein at least one, pereferably at least two of R8, R10 and R11are different from hydrogen,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

One preferred embodiment of the present invention relates to compoundsof Formula II, Ill or IV, wherein

R4 is hydrogen or fluoro, more preferably hydrogen,

R5 is hydrogen, iodo, or methyl,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl,ethyl, isopropyl, acetyl, trifluoromethyl, methoxy, ethoxy,fluoro(C₁₋₂)alkoxy, (C₁₋₂)alkoxymethoxy, cyanomethylsulfonyl, phenyl,phenoxy, benzyloxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl,3-thienyl, cyclopropyl, cyclopropyloxy, and cyclopropylmethoxy, or R6forms, together with R7 and the carbon atoms to which R6 and R7 areattached a ring selected from an unsubstituted or substituted phenyl,unsubstituted or substituted pyridyl, and unsubstituted or substitutedcyclopentyl, wherein any substitution is selected from fluoro, methoxyand methyl, wherein the ring is preferably selected from unsubstitutedphenyl, pyridyl or cyclopentyl,

and wherein in Formula II, if R6 is hydrogen, then R5 is iodo,

R7 is selected from hydrogen, methyl, methoxy, trifluoromethyl, fluoro,chloro and bromo,

X3 is N or C(R12), and is preferably C(R12),

R8 is selected from hydrogen, methoxy, cyano, chloro and fluoro,

R9 is selected from hydrogen and fluoro,

R10 is selected from hydrogen, ethynyl, cyano, cyanomethyl, acetyl,fluoro, chloro, bromo, iodo, azido, nitro, trifluoromethyl,difluoroethoxy, trifluoroethoxy, and pentafluorosulfanyl,

R11 is selected from hydrogen, fluoro, chloro, and methoxy,

R12 is hydrogen or fluoro

and wherein at least one of R8, R9, R10 and R11 is different fromhydrogen

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

One preferred embodiment of the present invention relates to compound ofFormula II, Ill IV or V, particularly preferably of Formula II or III,wherein

R4 is hydrogen,

R5 is selected from hydrogen, fluoro, chloro and bromo, and ispreferably hydrogen,

R6 is selected from fluoro, chloro, bromo, cyano, methyl, ethyl, propylpreferably isopropyl, methylsulfinyl, methylsulfonyl, cyclopropyl,cyclopropyloxy, benzyloxy, thienyl, methoxy, ethoxy, fluoro(C₁₋₃)alkoxyand fluoro(C₁₋₃)alkyl preferably trifluoromethyl,

R7 is selected from hydrogen, methoxy, fluoro, chloro, bromo, cyano,methylsulfinyl, methylsulfonyl, C₁₋₃alkoxy, fluoro(C₁₋₃)alkoxy,C₁₋₃alkyl and fluoro(C₁₋₃)alkyl preferably trifluoromethyl,

or, in compounds of Formula II, R6 and R7, together with thering-forming C atoms to which they are attached, may form a ringselected from phenyl, cyclopentyl and pyridyl, each of which may beunsubstituted or substituted with one or more residues selected fromfluoro, chloro, hydroxy, fluorinated or unsubstituted methoxy andfluorinated or unsubstituted methyl, wherein the phenyl, cyclopentyl andcyclohexyl rings are preferably unsubstituted and wherein the pyroidylring is preferably unsubstituted or substituted in 8-position, X3 is—C(R12)- or N,

R8 is hydrogen, fluoro, methoxy or fluoromethoxy, and is preferablyfluoro or methoxy,

R9 is hydrogen,

R10 is selected from halogen, azido, nitro, cyano, C₁₋₃alkyl,C₂₋₃alkenyl, C₂₋₃alkynyl, C₁₋₃ alkoxy, C₃₋₅cycloalkyl preferablycyclopropyl, C₃₋₅cycloalkyloxy and pentafluorosulfanyl, wherein eachalkyl, alkenyl, alkynyl and alkoxy can be unsubstituted or substitutedwith one or more residues selected from halogen preferanly fluoro,cyano, cyclopropyl, C₁₋₃alkoxy, and fluoroC₁₋₃alkoxy, and wherein anycycloalkyl moiety can be unsubstituted or substituted with one or moreresidues selected from fluoro, cyano, unsubstituted or fluorinatedC₁₋₃alkoxy and unsubstituted or fluorinated C₁₋₃alkoxycarbonyl,

R11 is selected from hydrogen, fluoro, chloro, cyano, methoxy,fluoromethoxy, and fluoromethyl, and

R12 is selected from hydrogen and fluoro,

wherein preferably at least one of R8 and R11 is different fromhydrogen, and wherein preferably at least one of R8 and R11 is selectedfrom fluoro, chloro and methoxy, and pharmaceutically acceptable salts,solvates, isotopes and co-crystals thereof.

One embodiment relates to compounds of Formula II, Ill IV and V,preferably of Formula II and III;

wherein

R4 and R5 are both hydrogen,

R6 is selected from methyl, ethyl, propyl, methylsulfonyl,methylsulfinyl, methoxy, mono-, di- and trifluoromethyl, mono-, di- andtrifluoroethyl, mono-, di- and trifluoromethoxy, mono-, di- andtrifluoroethoxy, cyano, azido, fluoro, bromo and chloro, and ispreferably selected from chloro and bromo,

R7, if present, is selected from hydrogen, fluoro, chloro, bromo, cyano,methoxy, fluoromethoxy, fluoroethoxy, methyl, fluoromethyl,methylsulfinyl and methylsulfonyl,

X3 is C(R12),

R8 is selected from hydrogen, fluoro, chloro and methoxy, or forms aring with R9 as described herein,

R9 forms together with R8 or R10 and the phenyl ring to which R8 and R9,or R9 and R10 are attached, a 2,1,3-benzothiadiazole or 1,3-benzodioxolewhich is optionally substituted with two fluoros,

R10 is selected from hydrogen and fluoro, or R10 forms a ring togetherwith R9 as described above,

R11 is selected from hydrogen, fluoro and methoxy,

R12 is hydrogen and pharmaceutically acceptable salts, solvates,isotopes and co-crystals thereof.

One preferred embodiment of the present invention relates to compound ofFormula II, Ill IV or V, particularly preferably of Formula II or III,wherein

R4, R5 are both hydrogen,

R6 is selected from fluoro, chloro, bromo, methoxy, fluoromethoxy andfluoromethyl,

R7 is selected from hydrogen, methoxy, fluoro, chloro, bromo,fluoromethyl preferably trifluoromethyl, fluoromethoxy, fluoroethoxy,methylsulfinyl and methylsulfonyl,

X3 is N or CR12,

R8 is fluoro or methoxy,

R9 is hydrogen,

R10 is selected from fluoro, chloro, bromo, cyano, cyanomethyl,cyanoethyl, cyanomethoxy, unsubstituted or fluorinated C₁₋₃ alkylpreferably methyl, ethyl and fluoromethyl, unsubstituted or fluorinatedC₁₋₃ alkoxy preferably fluoromethoxy and fluoroethoxy, unsubstituted orfluorinated C₁₋₂alkoxy(C₁₋₃)alkyl preferably methoxypropyl, fluorinatedmethoxypropyl, ethoxyethyl, and fluorinated methoxymethyl, unsubstitutedor fluorinated C₁₋₂alkoxy(C₂₋₃)alkenyl including methoxypropenyl andethoxyethenyl, unsubstituted or fluorinated C₁₋₂alkoxy(C₁₋₃)alkoxypreferably methoxyethoxy, pentafluorosulfanyl and cycloalkyl, which issubstituted with a substituent selected from C₁₋₂alkoxy,fluoro(C₁₋₂)alkoxy, C₁₋₂alkoxycarbonyl and fluoro(C₁₋₂)alkoxycarbonyl

R11 is selected from hydrogen, methoxy, fluoromethoxy, fluoromethyl, andfluoro,

R12, if present, is hydrogen or fluoro, and pharmaceutically acceptablesalts, solvates, isotopes and co-crystals thereof.

One preferred embodiment of the present invention relates to compound ofFormula II, Ill or IV, particularly preferably of Formula II or III,wherein

R4 and R5 are both hydrogen,

R6 is selected from fluoro, chloro, bromo, isopropyl, benzyloxy, andtrifluoromethyl,

R7 is hydrogen, methoxy, fluoro, or bromo, preferably hydrogen,

or R6 and R7, together with the ring-forming C atoms to which they areattached, form a ring selected from phenyl, cyclopentyl and pyridyl,

X3 is —C(R12)-,

R8 is fluoro, hydrogen, or methoxy,

R9 is hydrogen,

R10 is ethynyl, trifluoromethyl, difluoroethoxy, cyano, chloro, bromo,or iodo,

R11 is selected from hydrogen and fluoro, and

R12 is selected from hydrogen and fluoro, and pharmaceuticallyacceptable salts, solvates, isotopes and co-crystals thereof.

One embodiment relates to compounds of Formula II, Ill and IV,preferably of Formula II and III;

wherein

R4 and R5 are both hydrogen,

R6 is bromo or chloro, preferably chloro,

R7 is hydrogen, methoxy, fluoro or trifluoromethyl,

X3 is C(R12),

R8 is selected from hydrogen, fluoro, and methoxy, or forms a ring withR9 as described herein,

R9 forms together with R8 or R10 and the phenyl ring to which R8 and R9,or R9 and R10 are attached, a 2,1,3-benzothiadiazole or 1,3-benzodioxolewhich is optionally substituted with two fluoros,

R10 is selected from hydrogen and fluoro, or R10 forms a ring togetherwith R9 as described above,

R11 is selected from hydrogen, fluoro and methoxy,

R12 is hydrogen and pharmaceutically acceptable salts, solvates,isotopes and co-crystals thereof.

One preferred embodiment of the present invention relates to compound ofFormula II, Ill or IV, particularly preferably of Formula II or III,wherein

R4, R5 are hydrogen,

R6 is bromo, chloro, or trifluoromethyl,

R7 is hydrogen, methoxy, fluoro, or trifluoromethyl,

R8 is fluoro or methoxy,

R9 is hydrogen,

R10 is selected from fluoro, chloro, bromo, cyano, cyanomethyl,trifluoromethyl, difluoroethoxy, and pentafluorosulfanyl,

R11 is selected from hydrogen, methoxy and fluoro, and pharmaceuticallyacceptable salts, solvates, isotopes and co-crystals thereof.

One embodiment of the present invention relates to compounds of FormulaII, Ill, IV or V, preferably of Formula II or III, wherein

X3 is C(R12),

R4 is hydrogen or fluoro, preferably hydrogen,

R5 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, andtrifluoromethyl, preferably hydrogen , or R5 forms a ring together withR6 as described herein,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido,unsubstituted or substituted C₁₋₃ alkyl, preferably methyl, ethyl,isopropyl, or trifluoromethyl, C₁₋₂ alkylcarbonyl, C₁₋₂ alkoxycarbonyl,(C₁₋₃)alkylsulfinyl preferably methylsulfinyl, (C₁₋₃)alkylsulfonyl,preferably methylsulfonyl, unsubstituted or substituted benzylsulfonyl,unsubstituted or substituted benzylsulfinyl, C₃₋₆ cycloalkyl preferablycyclopropyl, C₃₋₆ cycloalkyl(C₁₋₃)alkyl preferably cyclopropylmethyl,C₃₋₆ heterocycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆ heterocycloalkoxy,unsubstituted or substituted C₁₋₃ alkoxy preferably methoxy, mono di-and trifluoroethoxy, unsubstituted or substitutedC₁₋₃alkoxy(C₁₋₃)alkoxy, preferably methoxyethoxy, unsubstituted orsubstituted C₁₋₃alkoxy(C₁₋₃)alkyl, (C₃₋₆)cycloalkyl(C₁₋₃)alkoxypreferably cyclopropylmethoxy, unsubstituted or substituted phenyl,unsubstituted or substituted phenyl(C₁₋₃)alkoxy preferably benzyloxy,unsubstituted or substituted phenyloxy, thienyl, pyridyl, oxazole,thiazole, and isoxazole, and wherein each optional substitution in R6 ispreferably selected from fluoro, chloro, unsubstituted or fluorinatedmethyl, unsubstituted or fluorinated methoxy, hydroxy, and cyano,provided that in the compounds of Formula III, if R6 is hydrogen, thenR5 is preferably iodo,

or

-   -   (i) R6 forms together with R7 and the carbon atoms to which R6        and R7 are attached, an unsubstituted or substituted phenyl, an        unsubstituted or substituted pyridyl, an unsubstituted or        substituted cyclopentyl or an unsubstituted or substituted        cyclohexyl,

wherein each substitution, if present, is selected from halogen,hydroxy, methyl or methoxy, wherein each methyl or methoxy can beunsubstituted or substituted with one or more substituents selected fromhalogen, preferably fluoro, and methoxy,

or

-   -   (ii) R6 forms together with R5 and the carbon atoms to which R6        and R5 are attached, a 1,3-dioxolane which may be unsubstituted        or substituted with one or two substituents selected from fluoro        and methyl,

R7 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, C₁₋₃alkyl, C₁₋₃ alkyloxy, fluoro(C₁₋₃)alkyl preferably trifluoromethyl,fluoro(C₁₋₃)alkoxy preferably fluoromethoxy or fluoroethoxy, C₁₋₂alkylcarbonyl, C₁₋₂ alkoxycarbonyl, methylsulfinyl, and methylsulfonyl,or R7 forms a ring together with R6 as described herein,

R8 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyloxypreferably methoxy, fluoro(C₁₋₃)alkoxy, C₁₋₃ alkyl preferably methyl,and fluoro(C₁₋₃)alkyl preferably trifluoromethyl,

R9 forms together with R10 and the ring to which they are attached abicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoselenadiazole, 2,1,3-benzoxadiazole,2-oxo-2,3-dihydro-1,3-benzoxazole, 1,3-benzothiazole,2,3-dihydro-1-benzothiophene, which is substituted with one or two oxo(preferably substituted with two oxo to give1,1-dioxo-2,3-dihydro-1-benzothiophene),3-oxo-1,3-dihydro-2-benzofuran-5-yl, which may be unsubstituted orsubstituted with one or two groups selected from oxo, fluoro and methyl,preferably with at least one oxo group to preferably form3-oxo-1,3-dihydro-2-benzofuran or1-methyl-3-oxo-1,3-dihydro-2-benzofuran, and dihydroisoindol which maybe unsubstituted or substituted with one or more substituents selectedfrom oxo, fluoro and methyl and which preferably is3-oxo-2,3-dihydro-1H-isoindol,and 1,3-benzodioxole, which is optionallysubstituted with one or two fluoros to preferably form2,2-difluoro-1,3-benzodioxol,

R11 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkylpreferably methyl, fluoro(C₁₋₃)alkyl preferably trifluoromethyl, C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃) alkoxy, preferablyfluoro(C₁₋₂)alkoxy, cyano, and, and is more preferably hydrogen, fluoro,chloro or bromo,

R12 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkyloxy preferablymethoxy, fluoro(C₁₋₃)alkoxy preferablyfluoro(C₁₋₂)alkoxy, C₁₋₃ alkyl preferably methyl, and fluoro(C₁₋₃)alkylpreferably trifluoromethyl, and is more preferably hydrogen, fluoro,chloro, or bromo,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

One embodiment of the present invention relates to compounds of FormulaII, Ill, or IV, preferably of Formula II or III, wherein

X3 is C(R12),

R4 is hydrogen,

R5 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, andtrifluoromethyl, preferably hydrogen or iodo, or R5 forms a ringtogether with R6 as described herein,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido,unsubstituted or substituted C₁₋₃ alkyl, preferably methyl, ethyl,isopropyl, or trifluoromethyl, C₁₋₂ alkylcarbonyl, C₁₋₂alkoxycarbonyl,(C₁₋₃)alkylsulfinyl preferably methylsulfinyl, (C₁₋₃)alkylsulfonyl,preferably methylsulfonyl, C₃₋₆ cycloalkyl preferably cyclopropyl, C₃₋₆cycloalkyl(C₁₋₃)alkyl preferably cyclopropylmethyl, C₃₋₆heterocycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆ heterocycloalkoxy,unsubstituted or substituted C₁₋₃ alkoxy preferably methoxy,unsubstituted or substituted C₁₋₃alkoxy(C₁₋₃)alkoxy, preferablymethoxyethoxy, (C₃₋₆)cycloalkyl(C₁₋₃)alkoxy preferablycyclopropylmethoxy, unsubstituted or substituted phenyl, unsubstitutedor substituted phenyl(C₁₋₃)alkoxy preferably benzyloxy, unsubstituted orsubstituted phenyloxy, thienyl, pyridyl, oxazole, thiazole, andisoxazole, and wherein each optional substitution in R6 is preferablyselected from fluoro, chloro, methyl, methoxy, and cyano,

provided that in the compounds of Formula II, if R6 is hydrogen, then R5is preferably iodo,

or

-   -   (i) R6 forms together with R7 and the carbon atoms to which R6        and R7 are attached, an unsubstituted or substituted phenyl, an        unsubstituted or substituted pyridyl, an unsubstituted or        substituted cyclopentyl or an unsubstituted or substituted        cyclohexyl,        -   wherein each substitution, if present, is selected from            halogen, methyl or methoxy, wherein each methyl or methoxy            can be unsubstituted or substituted with one or more            substituents selected from fluoro and methoxy,    -   or    -   (ii) R6 forms together with R5 and the carbon atoms to which R6        and R5 are attached, a 1,3-dioxolane which may be unsubstituted        or substituted with one or two substituents selected from fluoro        and methyl,

R7 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, C₁₋₃alkyl, C₁₋₃ alkyloxy, fluoro(C₁₋₃)alkyl preferably trifluoromethyl,fluoro(C₁₋₃)alkoxy preferably trifluoromethoxy, C₁₋₂ alkylcarbonyl,C₁₋₂alkoxycarbonyl, methylsulfinyl, and methylsulfonyl, or R7 forms aring together with R6 as described herein,

R8 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkyloxypreferably methoxy, fluoro(C₁₋₃)alkoxy, C₁₋₃ alkyl preferably methyl,and fluoro(C₁₋₃)alkyl preferably trifluoromethyl,

or R9 forms together with R10 and the ring to which they are attached abicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoselenadiazole, 2,1,3-benzooxadiazole,2-oxo-2,3-dihydro-1,3-benzoxazole, 1,3-benzothiazole,2,3-dihydro-1-benzothiophene, which is substituted with one or two oxo(preferably substituted with two oxo to give1,1-dioxo-2,3-dihydro-1-benzothiophene),3-oxo-1,3-dihydro-2-benzofuran-5-yl, and 1,3-benzodioxole, which isoptionally substituted with one or two fluoros,

R11 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkylpreferably methyl, fluoro(C₁₋₃)alkyl preferably trifluoromethyl, C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃) alkoxy, preferablyfluoro(C₁₋₂)alkoxy, cyano, and, and is more preferably hydrogen, fluoro,chloro or bromo,

R12 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkyloxy preferablymethoxy, fluoro(C₁₋₃)alkoxy preferablyfluoro(C₁₋₂)alkoxy, C₁₋₃ alkyl preferably methyl, and fluoro(C₁₋₃ )alkylpreferably trifluoromethyl, and is more preferably hydrogen, fluoro,chloro, or bromo,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

One preferred embodiment of the present invention relates to compound ofFormula II, Ill or Formula IV, particularly preferably of Formula II orIII, wherein

X3 is C(R12),

R4, R5 are both hydrogen,

R6 is selected from fluoro, chloro, bromo, methoxy, trifluoromethyl,methylsulfonyl, and cyano,

or R6 forms, together with R7 and the carbon atoms to which R6 and R7are attached a ring selected from an unsubstituted or substitutedphenyl, unsubstituted or substituted pyridyl, unsubstituted orsubstituted cyclohexyl, and unsubstituted or substituted cyclopentyl,wherein any substitution is selected from fluoro, methoxy and methyl,and wherein the ring is preferably selected from unsubstituted phenyl,pyridyl, cyclohexyl or cyclopentyl,

R7 is selected from hydrogen, methyl, fluoromethyl preferablytrifluoromethyl,methoxy, fluoro, chloro and bromo, preferably fromhydrogen, fluoro and trifluoromethyl, or R7 forms a ring together withR6 as described herein,

R8 is hydrogen or fluoro,

R9 together with R10 and the C atoms to which they are attached form aring selected from 2,1,3-benzothiadiazole, 2,1,3-benzoxadiazole,3-oxo-2,3-dihydro-1H-isoindol, 3-oxo-1,3-dihydro-2-benzofuran,1-methyl-3-oxo-1,3-dihydro-2-benzofuran,-and 2,2 difluoro-substituted1,3-benzodioxole, preferably a 2,1,3-benzothiadiazole,

R11 is hydrogen or fluoro, preferably hydrogen, and

R12 is hydrogen or fluoro, and pharmaceutically acceptable salts,solvates, isotopes and co-crystals thereof.

One preferred embodiment of the present invention relates to compound ofFormula II, Ill or Formula IV, particularly preferably of Formula II orIII, wherein

X3 is C(R12),

R4, R5 are both hydrogen,

R6 is fluoro, chloro, bromo, trifluoromethyl, methylsulfonyl, or cyano,

or R6 forms, together with R7 and the carbon atoms to which R6 and R7are attached a ring selected from an unsubstituted or substitutedphenyl, unsubstituted or substituted pyridyl, and unsubstituted orsubstituted cyclopentyl, wherein any substitution is selected fromfluoro, methoxy and methyl, and wherein the ring is preferably selectedfrom unsubstituted phenyl, pyridyl or cyclopentyl,

R7 is selected from hydrogen, methyl, trifluoromethyl, methoxy, fluoro,chloro and bromo, preferably from hydrogen and bromo, or R7 forms a ringtogether with R6 as described herein,

R8 is hydrogen or fluoro,

R9 together with R10 and the C atoms to which they are attached form aring selected from an 2,1,3-benzothiadiazole, 2,1,3-benzooxadiazole, and2,2 difluoro-substituted 1,3-benzodioxole, preferably a2,1,3-benzothiadiazole,

R11 is hydrogen or fluoro, and

R12 is hydrogen or fluoro, and pharmaceutically acceptable salts,solvates, isotopes and co-crystals thereof.

A further embodiment relates to compounds of Formula II, Ill IV or V,

wherein

X3 is C(R12),

R4 is hydrogen or fluoro, preferably hydrogen,

R5 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, andfluoromethyl, preferably hydrogen, or R5 forms a ring together with R6as described herein,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido,unsubstituted or substituted C₁₋₃ alkyl, preferably methyl, ethyl,propyl, mono-, di- and trifluoromethyl, unsubstituted or substitutedC₁₋₂ alkylcarbonyl, unsubstituted or substituted C₁₋₂ alkoxycarbonyl,(C₁₋₃) alkylsulfinyl preferably methylsulfinyl, (C₁₋₃)alkylsulfonyl,preferably methylsulfonyl, C₃₋₆ cycloalkyl preferably cyclopropyl, C₃₋ ₆cycloalkyl(C₁₋₃)alkyl preferably cyclopropylmethyl, C₃₋₆heterocycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆ heterocycloalkoxy,unsubstituted or substituted C₁₋₃alkoxy preferably methoxy, mono-, di-and trifluoromethoxy, mono-, di- and trifluoroethoxy, unsubstituted orsubstituted C₁₋₃alkoxy(C₁₋₃) alkoxy, preferably methoxyethoxy,unsubstituted or substituted C₁₋₃alkoxy(C₁₋₃)alkyl,(C₃₋₆)cycloalkyl(C₁₋₃)alkoxy preferably cyclopropylmethoxy,unsubstituted or substituted phenyl, unsubstituted or substitutedphenyl(C₁₋₃)alkoxy preferably benzyloxy, unsubstituted or substitutedphenyloxy, thienyl, pyridyl, oxazole, thiazole, and isoxazole, andwherein each optional substitution in R6 is preferably selected fromfluoro, chloro, methyl, methoxy, and cyano, provided that in thecompounds of Formula Ill, if R6 is hydrogen, then R5 is preferably iodo,

or

-   -   (i) R6 forms together with R7 and the carbon atoms to which R6        and R7 are attached, an unsubstituted or substituted phenyl, an        unsubstituted or substituted pyridyl, an unsubstituted or        substituted cyclopentyl or an unsubstituted or substituted        cyclohexyl,        -   wherein each substitution, if present, is selected from            halogen, hydroxy, methyl or methoxy, wherein each methyl or            methoxy can be unsubstituted or substituted with one or more            substituents selected from fluoro and methoxy,    -   or    -   (ii) R6 forms together with R5 and the carbon atoms to which R6        and R5 are attached, a 1,3-dioxolane which may be unsubstituted        or substituted with one or two substituents selected from fluoro        and methyl,

R7, if present, is selected from hydrogen, fluoro, chloro, bromo, iodo,cyano, C₁₋₃ alkyl, C₁₋₃ alkyloxy, fluoro(C₁₋₃)alkyl preferablytrifluoromethyl, fluoro(C₁₋₃)alkoxy preferably fluoromethoxy orfluoroethoxy, unsubstituted or fluorinated C₁₋₂ alkylcarbonyl,unsubstituted or fluorinated C₁₋₂ alkoxycarbonyl, methylsulfinyl,pyridylmethoxy, isoxazol and methylsulfonyl, or R7 forms a ring togetherwith R6 as described herein,

R9 forms together with R8 and the ring to which they are attached abicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoselenadiazole, 2,1,3-benzoxadiazole,2-oxo-2,3-dihydro-1,3-benzoxazole, and 1,3-benzodioxole, which isoptionally substituted with one or two fluoros,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyl,halo(C₁₋₃)alkyl, preferably fluoro(C₁₋₂)alkyl, halogenated preferablyfluorinated or unsubstituted C₁₋₃alkoxy(C₁₋₃)alkyl, C₂₋₃ alkynyl,halogenated preferably fluorinated or unsubstitutedC₁₋₃alkoxy(C₁₋₃)alkenyl, methoxy, ethoxy, halo(C₁₋₃)alkyloxy preferablyfluoro(C₁₋₂)alkoxy, halogenated preferably fluorinated or unsubstitutedC₁₋₃alkoxy(C₁₋₃)alkoxy, cyano, cyanomethyl, cyanoethyl, unsubstituted orfluorinated C₁₋₃alkylcarbonyl preferably acetyl, unsubstituted orfluorinated C₁₋₃alkoxycarbonyl preferably methoxycarbonyl,cyclopropylmethoxy, (C₁₋₂)alkoxycyclopropyl,(C₁₋₂)alkoxycarbonylcyclopropyl, azido, pentafluorosulfanyl, and nitro,and wherein in one embodiment, R10 is hydrogen, methoxy or halogen,

R11 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkylpreferably methyl, fluoro(C₁₋₃)alkyl preferably trifluoromethyl,C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃) alkoxy, preferablyfluoro(C₁₋₂)alkoxy, unsubstituted or fluorinated C₁₋₃alkylcarbonylpreferably acetyl, unsubstituted or fluorinated C₁₋₃alkoxycarbonylpreferably methoxycarbonyl and cyano, and is more preferably hydrogen,fluoro, chloro or bromo,

R12 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkyloxypreferably methoxy, fluoro(C₁₋₃)alkoxy preferably fluoro(C₁₋₂)alkoxy,C₁₋₃ alkyl preferably methyl, and fluoro(C₁₋₃)alkyl preferablytrifluoromethyl, and is more preferably hydrogen, fluoro, chloro, orbromo.

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

A further embodiment relates to compounds of Formula II, Ill or IV,

wherein

X3 is C(R12),

R4 is hydrogen,

R5 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, andtrifluoromethyl, preferably hydrogen or iodo, or R5 forms a ringtogether with R6 as described herein,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido,unsubstituted or substituted C₁₋₃alkyl, preferably methyl, ethyl,isopropyl, or trifluoromethyl, unsubstituted or substituted C₁₋₂alkylcarbonyl, unsubstituted or substituted C₁₋₂ alkoxycarbonyl, (C₁₋₃)alkylsulfinyl preferably methylsulfinyl, (C₁₋₃)alkylsulfonyl, preferablymethylsulfonyl, C₃₋₆ cycloalkyl preferably cyclopropyl, C₃₋₆cycloalkyl(C₁₋₃)alkyl preferably cyclopropylmethyl, C₃₋₆heterocycloalkyl, C₃₋₆ cycloalkoxy, C₃₋₆ heterocycloalkoxy,unsubstituted or substituted C₁₋₃ alkoxy preferably methoxy,unsubstituted or substituted C₁₋₃alkoxy(C₁₋₃) alkoxy, preferablymethoxyethoxy, (C₃₋₆)cycloalkyl(C₁₋₃)alkoxy preferablycyclopropylmethoxy, unsubstituted or substituted phenyl, unsubstitutedor substituted phenyl(C₁₋₃)alkoxy preferably benzyloxy, unsubstituted orsubstituted phenyloxy, thienyl, pyridyl, oxazole, thiazole, andisoxazole, and wherein each optional substitution in R6 is preferablyselected from fluoro, chloro, methyl, methoxy, and cyano, provided thatin the compound of Formula II, if R6 is hydrogen, then R5 is preferablyiodo,

or

-   -   (iii) R6 forms together with R7 and the carbon atoms to which R6        and R7 are attached, an unsubstituted or substituted phenyl, an        unsubstituted or substituted pyridyl, an unsubstituted or        substituted cyclopentyl or an unsubstituted or substituted        cyclohexyl,        -   wherein each substitution, if present, is selected from            halogen, methyl or methoxy, wherein each methyl or methoxy            can be unsubstituted or substituted with one or more            substituents selected from fluoro and methoxy,    -   or    -   (iv) R6 forms together with R5 and the carbon atoms to which R6        and R5 are attached, a 1,3-dioxolane which may be unsubstituted        or substituted with one or two substituents selected from fluoro        and methyl,

R7 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, C₁₋₃alkyl, C₁₋₃ alkyloxy, fluoro(C₁₋₃)alkyl preferably trifluoromethyl,fluoro(C₁₋₃)alkoxy preferably trifluoromethoxy, unsubstituted orfluorinated C₁₋₂ alkylcarbonyl, unsubstituted or fluorinated C₁₋₂alkoxycarbonyl, methylsulfinyl, and methylsulfonyl, or R7 forms a ringtogether with R6 as described herein,

R9 forms together with R8 and the ring to which they are attached abicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoselenadiazole, 2,1,3-benzooxadiazole,2-oxo-2,3-dihydro-1,3-benzoxazole, and 1,3-benzodioxole, which isoptionally substituted with one or two fluoros,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyl,halo(C₁₋₃)alkyl, preferably fluoro(C₁₋₂)alkyl, C₂₋₃ alkynyl, methoxy,ethoxy, halo(C₁₋₃)alkyloxy, preferably fluoro(C₁₋₂)alkoxy, cyano,cyanomethyl, unsubstituted or fluorinated C₁₋₃ alkylcarbonyl preferablyacetyl, unsubstituted or fluorinated C₁₋₃ alkoxycarbonyl preferablymethoxycarbonyl, azido, pentafluorosulfanyl, and nitro, and wherein inone embodiment, R10 is hydrogen, methoxy or halogen,

R11 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkylpreferably methyl, fluoro(C₁₋₃)alkyl preferably trifluoromethyl,C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃) alkoxy, preferablyfluoro(C₁₋₂)alkoxy, unsubstituted or fluorinated C₁₋₃ alkylcarbonylpreferably acetyl, unsubstituted or fluorinated C₁₋₃ alkoxycarbonylpreferably methoxycarbonyl and cyano, and is more preferably hydrogen,fluoro, chloro or bromo,

R12 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃)alkoxy preferablyfluoro(C₁₋₂)alkoxy, C₁₋₃ alkyl preferably methyl, and fluoro(C₁₋₃)alkylpreferably trifluoromethyl, and is more preferably hydrogen, fluoro,chloro, or bromo.

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

Another embodiment relates to compounds of Formula II, Ill IV or V,particularly preferably of Formula II or III, wherein

X3 is C(R12),

R4 and R5 are both hydrogen,

R6 is selected from fluoro, chloro, bromo, methoxy, fluoromethoxy,methylsulfinyl, methylsulfonyl, and fluoromethyl, and is preferablychloro, bromo or fluoromethyl,

or R6 forms, together with R7 and the carbon atoms to which R6 and R7are attached, a ring selected from an unsubstituted or substitutedphenyl, unsubstituted or substituted pyridyl, unsubstituted orsubstituted cyclohexyl, and unsubstituted or substituted cyclopentyl,wherein any substitution is selected from fluoro, fluorinated orunsubstituted methoxy and fluorinated or unsubstituted methyl, andwherein the ring is preferably selected from unsubstituted phenyl,pyridyl, cycloxexyl or cyclopentyl,

R7 is selected from hydrogen, fluoro, chloro, bromo, methoxy, methyl,acetyl, cyano, fluoromethyl, fluoromethoxy and fluoroethoxy, preferablyfrom hydrogen and trifluoromethyl, or R7 forms a ring together with R6as described herein,

R8 together with R9 and the C atoms to which they are attached form aring selected from 2,1,3-benzoselenadiazole, 2,1,3-benzothiadiazole,2,1,3-benzoxadiazole, unsubstituted 1,3-benzodioxole,2-oxo-2,3-dihydro-1,3-benzoxazole, and 2,2-difluoro-1,3-benzodioxole,

R10 is selected from hydrogen, fluoro, chloro, bromo and fluoromethyl,

R11 is selected from hydrogen, cyano, fluoro and chloro, and ispreferably hydrogen, and

R12 is selected from hydrogen, fluoro, chloro and fluoromethyl, andpharmaceutically acceptable salts, solvates, isotopes and co-crystalsthereof.

Another embodiment relates to compounds of Formula II, Ill or IV,particularly preferably of Formula II or III, wherein

X3 is C(R12),

R4 and R5 are both hydrogen,

R6 is selected from fluoro, chloro, bromo, and trifluoromethyl,

or R6 forms, together with R7 and the carbon atoms to which R6 and R7are attached a ring selected from an unsubstituted or substitutedphenyl, unsubstituted or substituted pyridyl, and unsubstituted orsubstituted cyclopentyl, wherein any substitution is selected fromfluoro, methoxy and methyl, and wherein the ring is preferably selectedfrom unsubstituted phenyl, pyridyl or cyclopentyl,

R7 is selected from hydrogen, fluoro, chloro, bromo, methoxy, methyl,acetyl and trifluoromethyl, preferably from hydrogen andtrifluoromethyl, or R7 forms a ring together with R6 as describedherein,

R8 together with R9 and the C atoms to which they are attached form aring selected from 2,1,3-benzothiadiazole, 2,1,3-benzooxadiazole,unsubstituted 1,3-benzodioxole, 2-oxo-2,3-dihydro-1,3-benzoxazole, and2,2-difluoro-1,3-benzodioxole,

R10 is hydrogen, or fluoro,

R11 is selected from hydrogen, fluoro, chloro, bromo and cyano, and

R12 is hydrogen, fluoro, chloro, and trifluoromethyl

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

Another embodiment relates to compounds of Formula II, Ill IV or V,particularly preferably of Formula II or III, wherein

X3 is C(R12),

R4 and R5 are both hydrogen,

R6 is selected from fluoro, chloro, bromo, and fluoromethyl,

or R6 forms, together with R7 and the carbon atoms to which R6 and R7are attached, a ring selected phenyl, pyridyl, cyclohexyl andcyclopentyl,

R7, if present, is selected from hydrogen, fluoro, chloro, bromo,methoxy, methyl, fluoromethyl, fluoromethoxy and fluoroethoxy,preferably from hydrogen, fluoro and trifluoromethyl, or R7 forms a ringtogether with R6 as described herein,

R8 together with R9 and the C atoms to which they are attached form aring selected from 2,1,3-benzothiadiazole, 2,1,3-benzoxadiazole, and2,2-difluoro-1,3-benzodioxole,

R10 is hydrogen or fluoro,

R11 is selected from hydrogen, fluoro and cyano, and

R12 is selected from hydrogen, fluoro and fluoromethyl,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

One embodiment relates to compounds of the general formula II, Ill, IVand V which are optionally substituted in 2-position of the upperbicyclic ring, thus having structures according to the general formulaII-2, III-2, IV-2 and V-2 as depicted below:

wherein R2 is selected from hydrogen, fluoro, chloro, bromo, iodo andmethoxy, and is preferably hydrogen or fluoro, particularly preferablyhydrogen,

and wherein R4, R5, R6, R7, if present, R8, R9, R10, R11 and X3 are asdescribed for the respective corresponding comounds of formula II, Ill,IV and V herein.

In one preferred embodiment of the present invention, in the compoundsof Formula II, II-2, III, III-2, IV, IV-2, V and V-2,

X3 is N or CR12,

R2, if present, R4, R5 and R9 are all hydrogen,

R6 is selected from halogen, cyano, C₁₋₃alkoxy, C₁₋₃alkyl,C₃₋₆cycloalkyl preferably C₃₋₄cycloalkyl, acycloalkyl, C₃₋₆cycloalkyloxypreferably C₃₋₄cycloalkyloxy, C₃₋₆heterocycloalkyl preferablyC₃₋₄heterocycloalkyl, and C₃₋₆heterocycloalkyloxy preferablyC₃₋₄heterocycloalkyloxy, each of which can be optionally substitutedwith a residue selected from fluoro and unsubstituted or fluorinatedC₁₋₃alkoxy,

R7 is selected from hydrogen, halogen, cyano, C₁₋₃alkoxy, C₁₋₃alkyl,C₃₋₆cycloalkyl preferably C₃₋₄cycloalkyl, C₃₋₆cycloalkyloxy preferablyC₃₋₄cycloalkyloxy, C₃₋₆heterocycloalkyl preferably C₃₋₄heterocycloalkyl,and C₃₋₆heterocycloalkyloxy preferably C₃₋₄heterocycloalkyloxy, each ofwhich can be optionally substituted with a residue selected from fluoroand unsubstituted or fluorinated C₁₋₃alkoxy,

R8 is selected from fluoro, methoxy and fluoromethoxy, preferably fromfluoro and methoxy,

R10 is selected from halogen, C₁₋₄alkoxy, C₁₋₄alkyl, C₂₋₃alkenylC₂₋₃alkynyl, C₃₋₆cycloalkyl preferably C₃₋₄cycloalkyl, C₃₋₆cycloalkyloxypreferably C₃₋₄cycloalkyloxy, C₃₋₆heterocycloalkyl preferablyC₃₋₄heterocycloalkyl, and C₃₋₆heterocycloalkyloxy preferablyC₃₋₄heterocycloalkyloxy, each of which can be optionally substitutedwith a residue selected from fluoro, cyano and unsubstituted orfluorinated C₁₋₃alkoxy, and

R11 is selected from hydrogen, fluoro, methoxy and fluoromethoxy,preferably from fluoro and methoxy,

and R12, if present is selected from hydrogen, fluoro, fluoromethyl,methoxy and fluoromethoxy.

In a further embodiment, the compounds of the present invention arerepresented by one of the following Form ulae Ila -IIc:

wherein

n is any number from 0 to 4,

m is 0 or 1,

p is any number from 0 to 3,

and

any Y is an independently selected substitution selected from the groupconsisting of halogen, hydroxy, cyano, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₃)alkyl, C₃₋₇heterocycloalkyl(C₁₋₃)alkyl, C₁₋₆ alkoxy, and C₁₋₆alkoxy(C₁₋₃)alkyl

wherein each alkyl or alkoxy can be unsubstituted or substituted withone or more substituents selected from halogen and C₁₋₃ alkoxy,

R4, R5, X3, R8, R9, R10, R11 and R12 are as described in the compoundsof Formula I, and II herein.

According to one embodiment, in the compounds of Formula II(a) to II(c)

m is 0 or 1, preferably 0,

n is any number from 0 to 4, preferably from 0 to 2, more preferably 0or 1,

p is any number from 0 to 3, preferably from 0 to 2, more preferably 0or 1,

any Y is an independently selected substitution selected from the groupof halogen, hydroxy, cyano, C₁₋₃alkyl, C₁₋₃alkoxy, andC₁₋₃alkoxy(C₁₋₃)alkyl wherein each alkyl or alkoxy can be unsubstitutedor substituted with one or more substituents selected from halogen andC₁₋₃ alkoxy,

R4 is hydrogen or fluoro, preferably hydrogen,

R5 is selected from hydrogen, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,wherein each alkyl or alkoxy may optionally be substituted one or moretimes, preferably with methoxy or halogen,

X3 is N or C(R12),

R8 is selected from hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, and halogen,wherein each alkyl or alkoxy can be unsubstituted or substituted withone or more substituents selected from halogen, cyano and methoxy, or R8forms a ring system together with R9, as described herein,

R9 is selected from hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, fluoro, chloro,bromo and iodo, wherein each alkyl or alkoxy can be unsubstituted orsubstituted with one or more substituents selected from halogen andmethoxy, and wherein R9 is preferably hydrogen, or R9 forms togetherwith R8 or R10 and the ring to which they are attached a bicyclic ringsystem selected from 2,1,3-benzothiadiazole, 2,1,3-benzoselenadiazole,2,1,3-benzoxadiazole, 1,3-benzoxazole which may optionally be partiallyhydrogenated and 2-oxo-substituted, 1,3-benzodioxole which may beunsubstituted or substituted with one or two substituents selected fromfluoro and methyl, 1,3-benzothiazole, 2,3-dihydro-1-benzothiophene,which is substituted with one or two oxo(preferably substituted with twooxo to give 1,1-dioxo-2,3-dihydro-1-benzothiophene), 3-oxo-2,3-dihydro-1H-isoindol, or 1,3 dihydro-2-benzofuran, which may be unsubstituted orsubstituted with one or two groups selected from oxo, fluoro and methyl,preferably with one oxo group, or with one oxo and one methyl group,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cyano, cyanomethyl, cyanoethyl,cyanomethoxy, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxycarbonyl, azido,pentafluorosulfanyl, and nitro, wherein each alkyl, alkenyl, alkynyl oralkoxy can be unsubstituted or substituted with one or more substituentsselected from halogen, cyano, hydroxy, fluoro(C₁₋₃)alkoxy andC₁₋₃alkoxy, or R8 forms a ring system together with R10, as describedherein,

R11 is selected from hydrogen, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkylcarbonyl,C₁₋₃ alkoxycarbonyl, fluoro, chloro, bromo, and iodo, wherein each alkyland alkoxy can be unsubstituted or substituted with one or moresubstituents selected from fluoro, chloro, bromo, iodo and C₁₋₃alkoxy,

R12, if present, is selected from hydrogen, C₁₋₃alkyl, C₁₋₃alkoxy,fluoro, chloro, bromo, and iodo, wherein each alkyl and alkoxy can beunsubstituted or substituted with one or more substituents selected fromfluoro, chloro, bromo, iodo and C₁₋₃alkoxy, wherein, in a preferredembodiment, at least one of R8, R10 and R11 is different from hydrogen,and more preferably at least one of R8, R9, R10 and R11 is alsodifferent from unsubstituted alkyl. ,and pharmaceutically acceptablesalts, solvates, isotopes and co-crystals thereof.

In one preferred embodiment, in the compounds having a structure ofFormula Ila, Ilb, and IIc, Y is selected from hydrogen, halogen,hydroxy, unsubstituted or fluorinated methyl and unsubstituted orfluorinated methoxy. In one embodiment, Y is fluoro, chloro, methoxy ortrifluoromethyl. In one preferred embodiment, the values for n and p areindependently 0, 1 or 2.

In another preferred embodiment, in the compounds having a structure ofFormula Ila, I lb, or lIc, the values for m, n and p are all 0.

In a particularly preferred embodiment of the compounds of Formula Ila,Ilb and IIc,

m is 0 or 1,

n and p are independently 0, 1 or 2,

Y is selected from halogen, hydroxy, fluorinated methyl andunsubstituted or fluorinated methoxy,

R4 is hydrogen,

R5 is hydrogen, methyl, methoxy, or halogen, preferably hydrogen,

X3 is N or C(R12),

R8 is selected from hydrogen, fluoro, chloro, bromo, methoxy,fluoromethoxy, and fluoromethyl, or R8 forms a ring system together withR9, as described herein,

R9 is hydrogen or fluoro, preferably hydrogen,

or R9 forms together with R8 or R10 and the ring to which they areattached a bicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoxadiazole, 1,3-benzodioxole,2-oxo-2,3-dihydro-1,3-benzoxazole, 2,2-difluoro-1,3-benzodioxole and4-methyl-2-oxodihydrobenzofuran,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl,cyano, cyanomethyl, cyanoethyl, cyanomethoxy, ethenyl, propenyl,ethynyl, propargyl, pentafluorosulfanyl, unsubstituted, fluorinated orhydroxylated C₁₋₃alkyloxy including mono-, di- and trifluoromethoxy andmono-, di- and trifluoroethoxy, unsubstituted or fluorinatedC₁₋₃3alkyloxy(C₁₋₃)alkyl, unsubstituted or fluorinatedC₁₋₃alkyloxy(C₁₋₃)alkyloxy, unsubstituted or fluorinatedC₁₋₃alkyloxy(C₂₋₃)alkenyl, unsubstituted or fluorinatedC₁₋₃alkyloxy(C₂₋₃)alkynyl, unsubstituted or fluorinated C₁₋₃alkylincluding trifluoromethyl, and cyclopropyl which is substituted with asubstituent selected from hydroxy, hydroxymethyl, C₁₋₂ alkoxy and C₁₋₂alkoxycarbonyl,

or R10 forms a ring system together with R9, as described herein,

R11 is selected from hydrogen, fluoro, chloro, and methoxy,

R12, if present, is selected from hydrogen, and fluoro,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof,

wherein in one preferred embodiment, if R9 does not form a ring with R8or R10, then R10 is not hydrogen, and, more preferably, R8 and R10 areboth not hydrogen.

In a particularly preferred embodiment of the compounds of Formula Ila,Ilb and IIc,

the values for m, n and p are all 0,

R4 is hydrogen,

R5 is hydrogen, methyl, methoxy, or halogen, preferably hydrogen,

X3 is N or C(R12),

R8 is selected from hydrogen, fluoro, chloro, bromo, methoxy,fluoromethoxy, and mono-, di-, and trifluoromethyl, and is preferablyselected from fluoro and methoxy, or R8 forms a ring system togetherwith R9, as described herein,

R9 is hydrogen or fluoro, preferably hydrogen,

or R9 forms together with R8 or R10 and the ring to which they areattached a bicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoxadiazole, 1,3-benzodioxole,2-oxo-2,3-dihydro-1,3-benzoxazole, or 2,2-difluoro-1,3-benzodioxole,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano,cyanomethyl, cyanoethyl, cyanomethoxy, pentafluorosulfanyl,fluoro(C₁₋₂)alkoxy preferably difluoroethoxy or trifluoroethoxy, andfluoro(C₁₋₂)alkyl preferably trifluoromethyl, or R10 forms a ring systemtogether with R9, as described herein,

R11 is selected from hydrogen, fluoro, chloro, methoxy andfluoromethoxy, preferably from fluoro and methoxy,

R12, if present, is selected from hydrogen, methoxy and fluoro, andpharmaceutically acceptable salts, solvates, isotopes and co-crystalsthereof, wherein in one preferred embodiment, if R9 does not form a ringwith R8, then R10 is not hydrogen, and more preferably, R8 and R10 areboth not hydrogen.

In a particularly preferred embodiment of the compounds of Formula Ila,Ilb and IIc,

the values for m, n and p are all 0,

R4 is hydrogen,

R5 is hydrogen, methyl, methoxy, or halogen, preferably hydrogen,

R8 is selected from hydrogen, fluoro, chloro, bromo, methoxy, andtrifluoromethyl, or R8 forms a ring system together with R9, asdescribed herein,

R9 is hydrogen or fluoro, preferably hydrogen,

or R9 forms together with R8 or R10 and the ring to which they areattached a bicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzooxadiazole, 1,3-benzodioxole,2-oxo-2,3-dihydro-1,3-benzoxazole, or 2,2-difluoro-1,3-benzodioxole,R10is selected from hydrogen, fluoro, chloro, bromo, cyano, cyanomethyl,pentafluorosulfanyl, difluoroethoxy, trifluoroethoxy, andtrifluoromethyl, or R10 forms a ring system together with R9, asdescribed herein, wherein, in a preferred embodiment, R8 and R10 are notboth hydrogen,

R11 is selected from hydrogen, fluoro, chloro, and methoxy,

R12 is selected from hydrogen, and fluoro,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

A further embodiment relates to compounds of Formula Ila to IIc, wherein

m is 0 or 1, preferably 0,

n is any number from 0 to 3, and is preferably 0 or 1,

p is any number from 0 to 2, and is preferably 0 or 1,

any Y is a substitution independently selected from the group ofhalogen, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, wherein each alkyl or alkoxycan be unsubstituted or substituted with one or more substituentsselected from halogen and C₁₋₃alkoxy,

R4 is hydrogen,

R5 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl,methoxy, and trifluoromethyl, and is preferably hydrogen,

X3 is N or C(R12),

R8 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyloxypreferably methoxy, fluoro(C₁₋₃)alkoxy, C₁₋₃alkyl preferably methyl, andfluoro(C₁₋₃)alkyl preferably trifluoromethyl,

R9 is selected from hydrogen, fluoro, chloro, or bromo, and ispreferably hydrogen,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkyloxy, cyano, unsubstituted orfluorinated C₁₋₃ alkylcarbonyl preferably acetyl, unsubstituted orfluorinated C₁₋₃ alkoxycarbonyl preferably methoxycarbonyl, azido,pentafluorosulfanyl, and nitro, wherein each alkyl, alkoxy, alkenyl oralkynyl can be optionally substituted with one or more substituentsselected from halogen, cyano, hydroxy, and unsubstituted or fluorinatedand/or hydroxylated C₁₋₃ alkoxy,

R11 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkylpreferably methyl, fluoro(C₁₋₃)alkyl preferably trifluoromethyl, C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃) alkoxy preferablyfluoro(C₁₋₂)alkoxy, unsubstituted or fluorinated C₁₋₃alkylcarbonylpreferably acetyl, unsubstituted or fluorinated C₁₋₃alkoxycarbonylpreferably methoxycarbonyl and cyano, and is more preferably hydrogen,fluoro, chloro or bromo,

R12, if present, is selected from hydrogen, fluoro, chloro, bromo, iodo,C₁₋₃ alkyloxy preferably methoxy, fluoro(C₁₋₃)alkoxy preferablyfluoro(C₁₋₂)alkoxy, C₁₋₃alkyl preferably methyl, and fluoro(C₁₋₃)alkylpreferably trifluoromethyl, and is more preferably hydrogen, fluoro,chloro, or bromo.

wherein, in a preferred embodiment, at least one of R8, R10 and R11 isdifferent from hydrogen, and preferably at least one of R8, R10 and R11is also different from unsubstituted alkyl,

wherein, in one preferred embodiment, R10 is different from hydrogen,and in a particularly preferred embodiment R10 and R8 are both nothydrogen, and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

A further embodiment relates to compounds of Formula Ila to IIc, wherein

m is 0 or 1, preferably 0,

n is any number from 0 to 3, and is preferably 0 or 1,

p is any number from 0 to 2, and is preferably 0 or 1,

any Y is a substitution independently selected from the group ofhalogen, C₁₋₃alkyl, C₁₋₃alkoxy, wherein each alkyl or alkoxy can beunsubstituted or substituted with one or more substituents selected fromhalogen and C₁₋₃alkoxy,

R4 is hydrogen,

R5 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl,methoxy, and trifluoromethyl, preferably hydrogen or iodo, and ispreferably hydrogen,

X3 is N or C(R12),

R8 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyloxypreferably methoxy, fluoro(C₁₋₃)alkoxy, C₁₋₃ alkyl preferably methyl,and fluoro(C₁₋₃)alkyl preferably trifluoromethyl,

R9 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkyloxypreferably methoxy, fluoro(C₁₋₃)alkoxy, C₁₋₃alkyl preferably methyl,cyano, and fluoro(C₁₋₃)alkyl preferably trifluoromethyl, and ispreferably hydrogen fluoro, chloro, or bromo,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkyl,halo(C₁₋₃)alkyl, preferably fluoro(C₁₋₃)alkyl, particularlytrifluoromethyl, C₂₋₃ alkynyl, C₁₋₃alkyloxy, halo(C₁₋₃) alkyloxy,preferably fluoro(C₁₋₂)alkoxy, cyano, cyanomethyl, unsubstituted orfluorinated C₁₋₃alkylcarbonyl preferably acetyl, unsubstituted orfluorinated C₁₋₃alkoxycarbonyl preferably methoxycarbonyl, azido,pentafluorosulfanyl, and nitro or R10 forms a ring system together withR9, as described herein,

R11 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkylpreferably methyl, fluoro(C₁₋₃)alkyl preferably trifluoromethyl,C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃) alkoxy, preferablyfluoro(C₁₋₂)alkoxy, unsubstituted or fluorinated C₁₋₃ alkylcarbonylpreferably acetyl, unsubstituted or fluorinated C₁₋₃ alkoxycarbonylpreferably methoxycarbonyl and cyano, and is more preferably hydrogen,fluoro, chloro or bromo,

R12 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkyloxypreferably methoxy, fluoro(C₁₋₃)alkoxy preferably fluoro(C₁₋₂)alkoxy,C₁₋₃ alkyl preferably methyl, and fluoro(C₁₋₃)alkyl preferablytrifluoromethyl, and is more preferably hydrogen, fluoro, chloro, orbromo.

wherein, in a preferred embodiment, at least one of R8, R9, R10 and R11is different from hydrogen, and more preferably at least one of R8, R9,R10 and R11 is also different from unsubstituted alkyl,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

Another preferred embodiment relates to compounds having a structure ofFormula Ila,

Ilb, or llc, wherein

m is 0 or 1,

n is 0, 1 or 2, and is preferably 0 or 1,

p is 0 or 1

any Y is selected from hydrogen, halogen, hydroxy, unsubstituted orfluorinated methyl and unsubstituted or fluorinated methoxy,

R4 and R5 are both hydrogen,

R8 is selected from hydrogen, methoxy, fluoromethoxy, fluoro, andchloro, and is preferably fluoro,

X3 is N or C(R12),

R9 is selected from hydrogen, methoxy, fluoro and chloro, and ispreferably hydrogen,

R10 is selected from hydrogen, ethynyl, cyano, cyanomethyl, cyanoethyl,cyanomethoxy, ethynyl, fluoro, chloro, bromo, iodo, azido,trifluoromethyl, trifluoromethoxy, difluoroethoxy, trifluoroethoxy andpentafluorosulfanyl,

R11 is selected from hydrogen, fluoro, chloro, and methoxy, and

R12, if present, is hydrogen or fluoro, and wherein at least one of R8,R9, R10 and R11 is different from hydrogen, and wherein, in a preferredembodiment, at least R10 is different from hydrogen and wherein in aparticularly preferred embodiment, R8 and R10 are both different fromhydrogen,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

Another preferred embodiment relates to compounds having a structure ofFormula Ila, Ilb, or lIc, wherein

m is 0 or 1,

n is 0, 1 or 2, and is preferably 0 or 1,

p is 0, 1 or 2,

any Y is selected from hydrogen, halogen, hydroxy, unsubstituted orfluorinated methyl

and unsubstituted or fluorinated methoxy,

R4 and R5 are both hydrogen,

R8 is fluoro or methoxy,

X3 is N or C(R12),

R9 is selected from hydrogen, methoxy, fluoro and chloro, and ispreferably hydrogen,

R10 is selected from halogen, ethynyl, propynyl, cyano, cyanomethyl,cyanoethyl, cyanomethoxy, unsubstituted or fluorinated (C₁₋₃)alkyl,unsubstituted or fluorinated (C₂₋₃)alkenyl, unsubstituted or fluorinated(C₂₋₃)alkynyl, unsubstituted or fluorinated C₁₋₃ alkyloxy, unsubstitutedor fluorinated methoxy(C₁₋₃)alkyl, unsubstituted or fluorinatedmethoxy(C₁₋₃)alkyloxy, unsubstituted or fluorinatedmethoxy(C₂₋₃)alkenyl, unsubstituted or fluorinated methoxy(C₂₋₃)alkynyland pentafluorosulfanyl,

R11 is selected from hydrogen, fluoro, and methoxy, and

R12, if present, is hydrogen or fluoro,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

In one preferred embodiment of the compounds of formula IIc, p is 1, andY is attached to the 8-position of the tricyclic ring system to give acompound of formula II-c1, wherein Y is preferably selected fromhalogen, methyl, fluoromethyl, methoxy, fluoromethoxy and hydroxy, andwherein X3, R4, R5, R8, R9, R10, and R11 are as described for thecompounds of Formula 11-c herein.

Another preferred embodiment relates to compounds having a structure ofFormula Ila,

Ilb, or IIc, wherein

m is 0 or 1,

n is 0, 1 or 2, and is preferably 0 or 1,

p is 0 or 1 or 2,

any Y is selected from hydrogen, halogen, hydroxy, unsubstituted orfluorinated methyl and unsubstituted or fluorinated methoxy,

R4 and R5 are both selected from hydrogen and fluoro,

R8 is fluoro or methoxy,

X3 is N,

R9 is selected from hydrogen, methoxy, fluoro and chloro, and ispreferably hydrogen,

R10 is selected from fluoro, chloro, bromo, ethynyl, propynyl, cyano,cyanomethyl, cyanoethyl, cyanomethoxy, unsubstituted or fluorinated(C₁₋₃)alkyl, unsubstituted or fluorinated (C₂₋₃)alkenyl, C₂₋₃alkynyl,unsubstituted or fluorinated C₁₋₃alkyloxy, unsubstituted or fluorinatedC₁₋₂alkoxy(C₁₋₃)alkyl, unsubstituted or fluorinatedC₁₋₂alkoxy(C₁₋₃)alkyloxy, unsubstituted or fluorinatedC₁₋₂alkoxy(C₂₋₃)alkenyl and pentafluorosulfanyl,

R11 is selected from hydrogen, fluoro, chloro, methoxy, fluoromethoxyand fluoromethyl, and pharmaceutically acceptable salts, solvates,isotopes and co-crystals thereof, wherein in a preferred embodiment, R10is selected from chloro, bromo, cyanomethyl, cyanoethyl, cyanomethoxy,unsubstituted or fluorinated (C₁₋₃)alkyl, unsubstituted or fluorinatedC₁₋₃alkyloxy, unsubstituted or fluorinated C₁₋₂alkoxy(C₁₋₂)alkyloxy andunsubstituted or fluorinated methoxy(C₁₋₃)alkyl, and is, in anotherpreferred embodiment, chloro.

Another preferred embodiment relates to compounds having a structure ofFormula Ila, Ilb, or IIc, wherein R10 is selected from halogen, cyano,cyanomethyl, and cyanoethyl.

Another preferred embodiment relates to compounds having a structure ofFormula Ila, Ilb, or llc, wherein

m is 0 or 1,

n is any number from 0 to 3, and is preferably 0 or 1,

p is any number from 0 to 2, and is preferably 0 or 1,

any Y is a substitution independently selected from the group ofhalogen, hydroxy, cyano, C₁₋₃ alkyl, C₁₋₃ alkoxy, wherein each alkyl oralkoxy can be unsubstituted or substituted with one or more substituentsselected from halogen, hydroxy and C₁₋₃ alkoxy,

X3 is C(R12),

R4 is hydrogen,

R5 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl,methoxy, and trifluoromethyl, preferably hydrogen or iodo,

R8 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyl,preferably methyl, and C₁₋₃ alkoxy, wherein R8 is preferably selectedfrom fluoro and methoxy,

or R9 forms together with R10 and the ring to which they are attached abicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoselenadiazole, 2,1,3-benzoxadiazole, 1,3-benzothiazole,2,3-dihydro-1-benzothiophene, which is substituted with one or two oxo(preferably substituted with two oxo to give1,1-dioxo-2,3-dihydro-1-benzothiophene), optionally methylated3-oxo-1,3-dihydro-2-benzofuran-5-yl, and 1,3-benzodioxole, which isoptionally substituted with one or two fluoros,

R11 is selected from hydrogen, fluoro, chloro, bromo, iodo and methoxy,and

R12 is selected from hydrogen, fluoro, chloro, bromo, methoxy,fluoromethoxy, methyl, and fluoromethyl.

Another preferred embodiment relates to compounds having a structure ofFormula Ila, Ilb, or llc, wherein

m is 0 or 1,

n is 0, 1 or 2, and is preferably 0,

p is 0 or 1, preferably 0,

any Y is selected from hydrogen, halogen, unsubstituted or fluorinatedmethyl and

unsubstituted or fluorinated methoxy,

R4, R5 are both hydrogen,

X3 is C(R12),

R8 is hydrogen, methoxy or fluoro, and is preferably hydrogen,

R9 together with R10 and the C atoms to which they are attached form aring selected from an 2,1,3-benzothiadiazole, 2,1,3-benzoxadiazole, and2,2-difluoro-1,3-benzodioxole, preferably 2,1,3-benzothiadiazole,

R11 is hydrogen or fluoro, and

R12 is hydrogen or fluoro

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

Another preferred embodiment relates to compounds having a structure ofFormula Ila, Ilb, or llc, wherein

m is 0 or 1,

n is any number from 0 to 3, and is preferably 0 or 1,

p is any number from 0 to 2, and is preferably 0 or 1,

any Y is a substitution independently selected from the group ofhalogen, hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, wherein each alkyl or alkoxycan be unsubstituted or substituted with one or more substituentsselected from halogen and C₁₋₃alkoxy,

X3 is C(R12),

R4 is hydrogen,

R5 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl,methoxy, and trifluoromethyl, preferably hydrogen or iodo,

R9 forms together with R8 and the ring to which they are attached abicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoselenadiazole, 2,1,3-benzoxadiazole,2-oxo-2,3-dihydro-1,3-benzoxazole, and 1,3-benzodioxole, which isoptionally substituted with one or two fluoros,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyl,halo(C₁₋₃)alkyl, preferably fluoro(C₁₋₃)alkyl, particularlytrifluoromethyl, C₂₋₃ alkynyl, C₁₋₃ alkyloxy, halo(C₁₋₃) alkyloxy,preferably fluoro(C₁₋₂)alkoxy, cyano, cyanomethyl, cyanoethyl,cyanomethoxy, unsubstituted or fluorinated C₁₋₃ alkylcarbonyl preferablyacetyl, unsubstituted or fluorinated C₁₋₃ alkoxycarbonyl preferablymethoxycarbonyl, azido, pentafluorosulfanyl, and nitro, wherein R10 ispreferably hydrogen, fluoro, chloro or bromo,

R11 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkylpreferably methyl, fluoro(C₁₋₃)alkyl preferably trifluoromethyl, C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃) alkoxy, preferablyfluoro(C₁₋₂)alkoxy, unsubstituted or fluorinated C₁₋₃ alkylcarbonylpreferably acetyl, unsubstituted or fluorinated C₁₋₃ alkoxycarbonylpreferably methoxycarbonyl and cyano, and is more preferably hydrogen,fluoro, chloro or bromo,

R12 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₃)alkoxy preferablyfluoro(C₁₋₂)alkoxy, C₁₋₃ alkyl preferably methyl, and fluoro(C₁₋₃)alkylpreferably trifluoromethyl, and is more preferably hydrogen, fluoro,chloro, or bromo,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

Another preferred embodiment relates to compounds having a structure ofFormula Ila, Ilb, or IIc, wherein

m is 0 or 1,

n is 0, 1 or 2, and is preferably 0,

p is 0 or 1 and is preferably 0,

any Y is selected from hydrogen, halogen, unsubstituted or fluorinatedmethyl and unsubstituted or fluorinated methoxy

X3 is C(R12)

R4 and R5 are both hydrogen,

R8 together with R9 and the ring to which they are attached form abicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoxadiazole, 2,1,3-benzoselanadiazole,2-oxo-2,3-dihydro-1,3-benzoxazole, unsubstituted 1,3-benzodioxole and2,2-difluoro-1,3-benzodioxole,

R10 is selected from the group of hydrogen, fluoro, chloro, bromo,trifluoromethyl, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, andcyano, and is preferably hydrogen or fluoro,

R11 is selected from hydrogen, methoxy, fluoro, chloro, bromo and cyano,and is preferably hydrogen or fluoro,

R12 is hydrogen, fluoro, chloro, and trifluoromethyl, andpharmaceutically acceptable salts, solvates, isotopes and co-crystalsthereof.

Another preferred embodiment relates to compounds having a structure ofFormula II,

wherein

R4 and R5 are both hydrogen or fluoro;

R6 is selected from fluoro, chloro, bromo, amino, nitro, cyano, azido,unsubstituted or fluorinated C₁₋₃alkyl preferably selected from methyl,ethyl, propyl preferably isopropyl, fluoromethyl preferablytrifluoromethyl, unsubstituted or fluorinated methylsulfonyl,unsubstituted or fluorinated methylsulfinyl, unsubstituted orfluorinated C₁₋₃alkyloxy preferably selected from methoxy, fluoromethoxyand fluoroethoxy, unsubstituted or fluorinatedC₁₋₂alkyloxy(C₁₋₂)alkyloxy including methoxyethoxy, cyclopropyl,cyclopropylmethoxy, phenyl, phenoxy, benzyloxy, benzylsulfinyl,2-thienyl, 3-thienyl, 3-pyridyl, 4-pyridyl, tetrahydrofuranyl,tetrahydrofuranylmethoxy and dimethyloxazole, wherein each phenyl,phenoxy, benzyloxy, 2-thienyl, 3-thienyl, 3-pyridyl, 4-pyridyl residuemay be optionally substituted with one or more of fluoro, chloro,unsubstituted or fluorinated methyl or unsubstituted or fluorinatedmethoxy,

X3 is C(R12) or N,

R7 is selected from hydrogen, methyl, fluoro(C₁₋₂)alkyl preferablymono-, di- or trifluoromethyl, methylsulfonyl, methylsulfinyl, methoxy,fluoro(C₁₋₂)alkoxy, cyano, pyridyl, pyridylmethoxy, phenoxy, oxazol,isoxazol, cyano, fluoro, chloro or bromo, and is preferably hydrogen,methoxy, fluoro, or bromo, wherein each pyridyl, isoxazol and phenylresidue may be optionally substituted with one or more of fluoro,chloro, unsubstituted or fluorinated methyl or unsubstituted orfluorinated methoxy;

R8 and R11 are independently selected from hydrogen, fluoro, chloro, andunsubstituted or fluorinated methoxy;

R9 is hydrogen,

R10 is selected from fluoro, chloro, bromo, iodo, acetyl, azido, nitro,cyano, cyanomethyl, cyanothyl, cyanomethoxy, unsubstituted orfluorinated C₁₋₂alkoxycyclopropyl, unsubstituted or fluorinatedC₁₋₂alkoxycarbonylcyclopropyl, cyclopropylmethoxy, cyclopropylmethyl,unsubstituted or fluorinated C₁₋₃alkyl preferably selected from methyland trifluoromethyl, unsubstituted or fluorinated and/or hydroxylatedC₁₋₃alkoxy preferably selected from methoxy, difluoromethoxy,trifluoromethoxy, difluoroethoxy, and trifluoroethoxy, unsubstituted orfluorinated C₁₋₂alkoxy(C₁₋₃)alkyl preferably unsubstituted orfluorinated methoxypropyl, unsubstituted or fluorinatedC₁₋₂alkoxy(C₁₋₃)alkoxy including fluoromethoxyethoxy, unsubstituted orfluorinated C₂₋₃alkenyl, unsubstituted or fluorinated C₂₋₃alkynyl,preferably ethynyl unsubstituted or fluorinated C₁₋₂alkoxy(C₂₋₃)alkenylpreferably methoxypropenyl, unsubstituted or fluorinatedC₁₋₂alkoxy(C₂₋₃)alkynyl and pentafluorosulfanyl;

R12, if present, is hydrogen or fluoro,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

Another preferred embodiment relates to compounds having a structure ofFormula II wherein R4 and R5 are both hydrogen; R6 is selected fromfluoro, chloro, bromo, methyl, ethyl, isopropyl, trifluoromethyl,methylsulfonyl, methoxy, cyclopropyl, cyclopropylmethoxy, phenyl,phenoxy, benzyloxy, 2-thienyl, 3-thienyl, 3-pyridyl, 4-pyridyl,tetrahydrofuranyl and dimethyloxazole, X3 is C(R12), R9 is hydrogen; R7is selected from hydrogen, methyl, trifluoromethyl, methoxy, fluoro,chloro or bromo, and is preferably hydrogen, methoxy, or bromo; R8 andR11 are independently selected from hydrogen, fluoro, chloro, andmethoxy; R10 is fluoro, chloro, bromo, iodo, acetyl, azido, ethynyl,cyano, cyanomethyl, trifluoromethyl, difluoroethoxy, trifluoroethoxy, orpentafluorosulfanyl; R12 is hydrogen or fluoro, and pharmaceuticallyacceptable salts, solvates, isotopes and co-crystals thereof

Another embodiment relates to compounds of formula II, wherein

R4 is hydrogen or fluoro, preferably hydrogen;

R5 is selected from hydrogen, fluoro, chloro, bromo, methoxy andfluoromethoxy,

R6 is selected from halogen, cyano, amino, nitro, unsubstituted orfluorinated methylsulfonyl, unsubstituted or fluorinated methylsulfinyl,C₁₋₃alkyl, C₁₋₃alkyloxy, C₂₋₃ alkenyl, cyclopropyl, phenyl, phenoxy,benzyloxy, benzylsulfinyl, 2-thienyl, 3-thienyl, 3-pyridyl, and4-pyridyl, wherein each phenyl, phenoxy, benzyloxy, 2-thienyl,3-thienyl, 3-pyridyl, 4-pyridyl may be optionally substituted with oneor more of fluoro, chloro, unsubstituted or fluorinated methyl orunsubstituted or fluorinated methoxy, and wherein each alkyl, alkenyland alkoxy group can be unsubstituted or substituted with one or moregroup selected from halogen, methoxy, fluoromethoxy, cyano, cyclopropyl,and halogen,

X3 is C(R12) or N,

R7 is selected from hydrogen, cyano, fluoro, chloro, bromo,unsubstituted or fluorinated C₁₋₃alkyl preferably selected from methyl,fluoromethyl and fluoroethyl, and unsubstituted or fluorinatedC₁₋₃alkyloxy preferably selected from methoxy, fluoromethoxy andfluoroethoxy,

R8 and R11 are independently selected from hydrogen, fluoro, chloro,cyano, methyl, fluoromethyl, methoxy and fluoromethoxy;

R9 is hydrogen or fluoro, preferably hydrogen,

R10 is selected from halogen, azido, cyano, cyclopropyl, nitro,C₁₋₃alkyl, C₁₋₃alkoxy, C₂₋₃ alkenyl, C₂₋₃ alkynyl,C₁₋₃alkylcarbonyl(C₁₋₃)alkyl, C₁₋₃alkoxycarbonyl(C₁₋₃)alkyl andpentafluorosulfanyl, wherein each alkyl, alkenyl, alkynyl and alkoxygroup can be unsubstituted or substituted with one or more residuesselected from fluoro, chloro, cyano, cyclopropyl and unsubstituted orfluorinated and/or hydroxylated C₁₋₃alkoxy, and wherein each cyclopropylgroup can be substituted with one or more residues selected fromhalogen, hydroxy, hydroxymethyl, C₁₋₃alkoxy, C₁₋₃alkoxycarbonyl andcyano,

R12, if present, is hydrogen or fluoro, and pharmaceutically acceptablesalts, solvates, isotopes and co-crystals thereof.

Another embodiment relates to compounds of Formula II wherein

R4 is hydrogen,

R5 is selected from hydrogen, fluoro, chloro and bromo,

R6 is selected from fluoro, chloro, bromo, iodo, cyano, nitro, methyl,ethyl, isopropyl, fluoromethyl preferably trifluoromethyl, fluoroethyl,methoxy, fluoromethoxy, fluoroethoxy, cyano, methylsulfinyl,methylsulfonyl, cyclopropyl, phenyl, benzyloxy, 2-thienyl and 3-thienyl,

R7 is selected from hydrogen, fluoro, chloro, bromo, cyano,fluoro(C₁₋₂)alkyl preferably trifluoromethyl, and fluoro(C₁₋₂)alkoxy,and is preferably selected from hydrogen, fluoro, methoxy, fluoromethoxyand fluoroethoxy,

X3 is C(R12),

R8 and R11 are independently selected from hydrogen, fluoro, chloro,cyano, fluoromethyl, methoxy and fluoromethoxy,

R9 is hydrogen,

R10 is selected from fluoro, chloro, bromo, iodo, azido, unsubstitutedor fluorinated C₁₋₃alkyl preferably trifluoromethyl, unsubstituted orfluorinated C₁₋₃alkyloxy preferably selected from difluoroethoxy,trifluoromethoxy and trifluoroethoxy, unsubstituted or fluorinatedC₁₋₃alkoxy(C₁₋₃)alkyl, unsubstituted or fluorinatedC₁₋₃alkoxy(C₁₋₃)alkoxy, unsubstituted or fluorinatedC₁₋₃alkoxy(C₂₋₃)alkenyl, pentafluorosulfanyl, ethynyl, propynyl, cyano,cyanomethoxy, and cyanomethyl, and

R12 is hydrogen and fluoro,

wherein preferably at least one of R8 and R11 is fluoro or chloro,preferably fluoro.

Another embodiment relates to compounds of Formula II wherein R4 and R5are both hydrogen, R6 is selected from fluoro, chloro, bromo, iodo,methyl, isopropyl, trifluoromethyl, methylsulfonyl, cyclopropyl, phenyl,benzyloxy, 2-thienyl and 3-thienyl, X3 is C(R12), R7 is selected fromhydrogen, methyl, methoxy, fluoro, chloro, bromo and trifluoromethyl,preferably from hydrogen, fluoro, and bromo, R8 and R11 areindependently selected from hydrogen, fluoro, chloro and methoxy, R9 ishydrogen, R10 is selected from hydrogen, fluoro, chloro, bromo, iodo,azido, trifluoromethyl, difluoroethoxy, trifluoromethoxy,trifluoroethoxy, pentafluorosulfanyl, ethynyl, cyano and cyanomethyl,R12 is hydrogen and fluoro, wherein preferably at least one of R8 andR11 is fluoro or chloro, preferably fluoro.

Another embodiment relates to compounds of Formula II wherein R4 and R5are both hydrogen, R6 is selected from fluoro, chloro, bromo, isopropyl,trifluoromethyl, cyclopropyl, methoxy, fluoromethoxy, fluoroethoxy,methylsulfinyl, and benzyloxy, R7 is hydrogen, methyl, methoxy,fluoromethoxy, fluoroethoxy, fluoromethyl, cyano, bromo, or fluoro, X3is C(R12), R9 is hydrogen, R10 is selected from fluoro, bromo, chloro,iodo, methyl, fluoromethyl preferably trifluoromethyl,fluoro(C₁₋₂)alkoxy preferably difluoroethoxy and trifluoromethoxy,pentafluorosulfanyl, cyano, cyanomethoxy, cyanomethyl and cyanoethyl,R12 is hydrogen or fluoro, and R8 and R11 are independently selectedfrom hydrogen, fluoro, chloro, methoxy and fluoromethoxy, and are, inone preferred embodiment, both different from hydrogen.

Another embodiment relates to compounds of Formula II wherein R4, and R5are both hydrogen, R6 is selected from fluoro, chloro, bromo, isopropyl,trifluoromethyl, cyclopropyl, and benzyloxy, R7 is hydrogen, methoxy, orfluoro, X3 is C(R12), R9 is hydrogen, R10 is selected from fluoro,bromo, chloro, iodo, trifluoromethyl, difluoroethoxy, trifluoromethoxy,pentafluorosulfanyl, cyano, and cyanomethyl, R12 is hydrogen or fluoro,and R8 and R11 are both different from hydrogen and are preferablyfluoro, chloro, methoxy or cyano, more preferably fluoro.

Another preferred embodiment relates to compounds of Formula II whereinR4 and R5 are both hydrogen, R6 is selected from fluoro, chloro, bromo,isopropyl, fluoromethyl, methoxy, fluoromethoxy and phenyloxy, R7 ishydrogen, methoxy, fluoromethoxy, fluoroethoxy, cyano, fluoro or chloro,X3 is C(R12), R9 is hydrogen or fluoro, R10 is hydrogen, R12 is hydrogenor fluoro, and R8 and R11 are both independently selected from fluoro,chloro and methoxy.

Another preferred embodiment relates to compounds of Formula II whereinR4, and R5 are both hydrogen, R6 is selected from fluoro, chloro, bromo,isopropyl, trifluoromethyl, and phenyloxy, R7 is hydrogen, methoxy orfluoro, X3 is C(R12), R9 is hydrogen or fluoro, R10 is hydrogen, R12 ishydrogen or fluoro, and R8 and R11 are both independently selected fromfluoro, chloro and cyano.

Another preferred embodiment relates to compounds of Formula II whereinR4 and R5 are both hydrogen, R6 is selected from fluoro, chloro, bromo,iodo, methyl, ethyl, isopropyl, fluoromethyl preferably trifluoromethyl,methoxy, methylsulfinyl, methylsulfonyl, cyclopropyl, phenyl, benzyloxy,2-thienyl and 3-thienyl, and preferably from fluoro, chloro, bromo, andtrifluoromethyl, R7 is hydrogen, methoxy or fluoro, preferably hydrogen,X3 is C(R12), R8 is hydrogen, R9 and R10, together with the C atoms towhich they are attached form a 2,1,3-benzothiadiazole,3-oxo-1,3-dihydro-2-benzofuran, or1-methyl-3-oxo-1,3dihydro-2-benzofuran and R11 and R12 are independentlyselected from hydrogen and fluoro.

Another embodiment relates to compounds of Formula II wherein R4, and R5are both hydrogen, R6 is selected from fluoro, chloro, bromo andmethylsulfonyl, R7 is selected from hydrogen, fluoro, bromo, chloro,methoxy, and trifluoromethyl, X3 is C(R12), R8 and R9 together with thering to which they are attached form a 2,1,3-benzothiadiazole,2,1,3-benzoselenadiazole, 2,1,3-benzoxadiazole or optionally2,2-fluoro-substituted 1,3-benzodioxole, R10 is hydrogen, fluoro, orbromo, R11 is selected from hydrogen, fluoro and cyano, and R12 ishydrogen, fluoro or trifluoromethyl.

Another embodiment relates to compounds of Formula II wherein R4 ishydrogen, R5 is selected from hydrogen and fluoro, R6 is selected fromfluoro, chloro, bromo, methoxy and trifluoromethyl, R7 is selected fromhydrogen, halogen, methylsulfonyl, methoxy, fluoromethoxy, fluoroethoxyand fluoromethyl preferably trifluoromethyl, X3 is N, R8 is fluoro,chloro or methoxy, R9 is selected from hydrogen, fluoro, chloro, methyland methoxy and is preferably hydrogen, R10 is selected from fluoro,chloro, bromo, cyano, cyanomethyl, cyanoethyl, pentafluorosulfanyl,mono-, di- and trifluoromethyl, mono-, di- and and trifluoromethoxy,mono-, di- and trifluoroethoxy, unsubstituted or fluorinatedC₁₋₂alkoxy(C₁₋₃)alkyl, unsubstituted or fluorinatedC₁₋₂alkoxy(C₁₋₂)alkoxy, ethynyl and cyanomethyl, and R11 is selectedfrom hydrogen, fluoro, chloro, fluoromethyl, methoxy and fluoromethoxy.

Another embodiment relates to compounds of Formula II wherein R4, R5 areboth hydrogen, R6 is selected from fluoro, chloro, bromo and methoxy, R7is selected from , hydrogen, fluoro, chloro, bromo, fluorometyl, methoxyand fluoromethoxy, X3 is N, R8 is fluoro or methoxy, R9 is hydrogen, R10is selected from fluoro, chloro, bromo, cyano, cyanomethyl, acetyl,methyl, ethyl, ethoxyethyl, methoxypropyl, fluorinated methoxypropyl,fluoromethyl, fluoromethoxymethyl, methoxycarbonylcyclopropyl,ethoxycarbonylcyclopropyl, ethenyl, ethoxyethenyl, methoxy,fluoromethoxy, fluoroethoxy, fluoropropoxy, methoxyethoxy, fluorinatedmethoxyethoxy, ethoxyethoxy, fluorinated ethoxyethoxy, methoxypropoxy,fluorinated methoxypropoxy, methoxypropenyl, and fluoromethoxypropenyl,and R11 is hydrogen, methoxy, fluoro or chloro.

Another embodiment relates to compounds of Formula II wherein R4 and R5are both hydrogen, R6 is chloro or bromo, R7 is selected from hydrogen,fluoro, chloro, bromo and methoxy, and X3 is C(R12) or N, R8 is fluoro,chloro or methoxy, R9 is hydrogen or fluoro, preferably hydrogen, R10 isselected from fluoro, chloro, bromo, cyano, C₁₋₃alkyl, C₂₋₃alkenyl andC₁₋₃alkoxy, wherein each alkyl, alkenyl and alkoxy can be unsubstitutedor substituted with one or more substituents selected from halogen,preferably fluoro, cyano, C₁₋₂alkoxy and fluoro(C₁₋₂)alkoxy, and R11 ishydrogen, fluoro or methoxy.

Another embodiment relates to compounds having Formula II(d), II(e),II(f) and II(g),

wherein R4, R5, R6, R7, R8, R10, R11 and R12 are as otherwise describedfor Formulae I and II herein,

wherein in Formula II(d), Q1 is S or O, and

wherein in Formula II(e), R13 and R14 are selected from the group ofhydrogen, methyl and fluoro and are preferably either both hydrogen orboth fluoro,

wherein in Formula II(f), Q2 is S or O, preferably S, and wherein inFormula II (g), R16 is selected from hydrogen, fluoro, hydroxy, methyl,fluoromethyl, methoxy and fluoromethoxy, and is preferably selected fromhydrogen and methyl,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

One embodiment relates to compounds according to Formulae II(d), II(e),II(f) and II(g),

wherein

wherein in Formula II(d), Q1 is S or O, and

wherein in Formula II(e), R13 and R14 are both selected from hydrogenand fluoro,

wherein in Formula II(f), Q2 is S or O, preferably S,

wherein in Formula II(g), R16 is selected from hydrogen and methyl,

R4 is hydrogen,

R5 is selected from hydrogen, fluoro, chloro and bromo, and ispreferably hydrogen,

R6 is selected from fluoro, chloro, bromo, methyl, methoxy,methylsulfonyl, methylsulfinyl, fluoromethyl, fluoromethoxy, cyano, andbenzyloxy, preferably from fluoro, chloro, bromo and fluoromethyl,

R7 is selected from hydrogen, fluoro, chloro, bromo, methoxy, cyano,methyl, and fluoromethyl, preferably from hydrogen and mono-, di-, andtrifluoromethyl,

R8, if present, is selected from hydrogen and halogen, preferably fromhydrogen and fluoro, and is more preferably hydrogen,

R10, if present, is selected from hydrogen, fluoro, chloro, bromo, andcyano, preferably hydrogen or fluoro,

R11 is selected from hydrogen, halogen, methoxy, fluoromethoxy,fluoromethyl and cyano, and is preferably hydrogen or fluoro,

R12 is selected from hydrogen, halogen, methoxy, fluoromethyl,preferably from hydrogen, fluoro, and fluoromethyl,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

In a preferred embodiment of the compounds of Formula Ild and Ile,

R4 and R5 are both hydrogen,

R6 is selected from fluoro, chloro, bromo, trifluoromethyl, and phenyl,

R7 is hydrogen, fluoro, bromo, methoxy, or trifluoromethyl, preferablyhydrogen or trifluoromethyl,

R10 is selected from hydrogen and halogen, preferably from hydrogen,fluoro and chloro,

R11 is selected from hydrogen, halogen, trifluoromethyl and cyano,preferably from fluoro and hydrogen,

R12 is selected from hydrogen, halogen and trifluoromethyl, preferablyfrom fluoro and hydrogen,

R13 and R14, in formula Ile, are both selected from hydrogen and fluoro,and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

In a preferred embodiment of the compounds of Formula II(f),

R4 and R5 are both hydrogen,

R6 is selected from fluoro, chloro, bromo, trifluoromethyl and phenyl,

R7 is selected from hydrogen, methoxy, fluoro, and trifluoromethyl,

R8 is selected from hydrogen and halogen, preferably from hydrogen andfluoro,

R11 is selected from hydrogen, halogen, trifluoromethyl and cyano, andis preferably hydrogen,

R12 is selected from hydrogen, halogen and trifluoromethyl, preferablyfrom fluoro and hydrogen,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

One embodiment relates to compounds of subformula Ila, Ilb, IIc, Ild,Ile, Ilf, and Ilg, which are additionally substituted with a group R2,as depicted for the general Formula II-2 above, thus leading to therespective corresponding compounds having subformula II-2a, II-2b,II-2c, II-2d, II-2e, II-2f, and II-2g, wherein R2 is selected fromhydrogen, fluoro, chloro, bromo, iodo and methoxy, and wherein R2 ispreferably hydrogen or fluoro, and particularly preferably hydrogen, andwherein the other residues are as defined in the formula II-2a, II-2b,II-2c, II-2d, II-2e, II-2f, and II-2g, herein. By way of non-limitingexample, Formula II-2d and II-2f are depicted below:

Another preferred embodiment relates to compounds having a structure ofFormula III,

wherein R4 and R5 are both hydrogen,

R6 is selected from hydrogen, fluoro, chloro, bromo, fluoromethyl,methoxy, fluoromethoxy, and cyclopropyl,

X3 is C(R12) or N,

R8 is selected from hydrogen, methoxy, and halogen, particularlypreferably from fluoro, chloro, methoxy and hydrogen,

R9 is hydrogen,

R10 is selected from fluoro, bromo, chloro, iodo, methyl,fluoro(C₁₋₃)alkyl preferably trifluoromethyl, unsubstituted orfluorinated methoxy(C₁₋₃)alkyl, unsubstituted or fluorinated

C₁₋₃alkyloxy preferably mono,- di- and trifluoromethoxy and mono-, di-and trifluoroethoxy, unsubstituted or fluorinated methoxy(C₁₋₃)alkyloxy,unsubstituted or fluorinated C₂₋₃alkenyl, unsubstituted or fluorinatedmethoxy(C₂₋₃)alkenyl, ethynyl, propargyl, unsubstituted or fluorinatedmethoxy(C₂₋₃)alkynyl, azido, pentafluorosulfanyl, cyanomethyl,cyanoethyl, and cyano,

R11 is hydrogen, fluoro, chloro, or methoxy, particularly preferablyhydrogen or fluoro,

R12, if present, is hydrogen or fluoro,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

Another embodiment relates to compounds of Formula Ill, wherein R4 andR5 are both hydrogen, R6 is chloro or bromo, X3 is C(R12), R12 ishydrogen or fluoro, R8 is selected from hydrogen, methoxy, and halogen,particularly preferably from fluoro and hydrogen, R9 is hydrogen, R10 isselected from fluoro, bromo, chloro, iodo, trifluoromethyl,difluoroethoxy, trifluoromethoxy, trifluoroethoxy, ethynyl, azido,acetyl, pentafluorosulfanyl, cyanomethyl, and cyano, R11 is hydrogen,fluoro, chloro, or methoxy, particularly preferably hydrogen or fluoro,and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

Another particularly preferred embodiment relates to a compound ofFormula Ill, wherein R4 and R5 are both hydrogen, R6 is selected frommethyl, fluoromethyl, methoxy, fluoromethoxy, chloro or bromo, X3 isC(R12), R8 is hydrogen, methoxy, or fluoro and is preferably fluoro, R9is hydrogen, R10 is selected from fluoro, bromo, chloro, iodo, mono-,di- and trifluoromethyl, mono-, di- and trifluoromethoxy, mono-, di-,and trifluoroethoxy, pentafluorosulfanyl, ethynyl and cyano, and R11 andR12 are independently selected from hydrogen and fluoro.

Another preferred embodiment relates to compounds of Formula Ill,wherein R4 and R6 are hydrogen, R5 is iodo, X3 is C(R12) or N, R8 andR11 are both independently selected from hydrogen or fluoro, R10 isselected from fluoro, bromo, chloro, iodo, mono-, di- andtrifluoromethyl, mono-, di-, and trifluoromethoxy, mono-, di-, andtrifluoroethoxy, pentafluorosulfanyl, and cyano, R9 is hydrogen, andR12, if present, is hydrogen or fluoro,

Another preferred embodiment relates to a compound of Formula Ill,wherein R4 and R5 are both hydrogen, R6 is chloro or bromo, X3 isC(R12), R8 is hydrogen, R9 and R10, together with the phenyl ring towhich they are attached, form a 2,1,3-benzothiadiazole ring system, R11is hydrogen and R12 is fluoro or hydrogen.

Another preferred embodiment relates to a compound of Formula Ill,wherein R4 and R5 are both hydrogen, R6 is chloro or bromo, X3 isC(R12), R8 and R9, together with the phenyl ring to which they areattached, form a 2,1,3-benzothiadiazole, 2,1,3-benzoxadiazole,unsubstituted 1,3-benzoxolane, or 2,3,-difluoro-1,3-benzoxalane group,

R10 and R11 are independently selected from hydrogen, methoxy, cyano andhalogen, preferably from hydrogen and fluoro, and R12 is fluoro,trifluoromethyl or hydrogen.

Another embodiment relates to compounds of Formula III, wherein R4 andR5 are both hydrogen, R6 is selected from fluoro, chloro, bromo andmono-, di-, and trifluoromethyl, X3 is N, R8 is fluoro, chloro ormethoxy, R9 is selected from hydrogen, fluoro, chloro, and methoxy, andis preferably hydrogen, R10 is selected from fluoro, chloro, bromo,iodo, cyano, mono-, di and trifluoromethyl, mono-, di-, andtrifluoromethoxy, mono-, di-, and trifluoroethoxy, ethynyl andcyanomethyl, and R11 is hydrogen, fluoro or chloro.

Another embodiment relates to compounds of Formula III, wherein R4 andR5 are both hydrogen, R6 is selected from chloro, bromo, methoxy, mono-,di-, and trifluoromethyl, X3 is C(R1 2) or N, R8 is selected fromhydrogen, fluoro, chloro, methoxy and fluoromethoxy, R9 is hydrogen, R10is selected from fluoro, chloro, bromo, cyano, cyanomethyl, cyanoethyl,cyanomethoxy, mono-, di-, and trifluoromethyl, mono-, di-, andtrifluoromethoxy, mono-, di-, and trifluoroethoxy, unsubstituted orfluorinated C₁₋₂alkoxy(C₁₋₃) alkoxy, unsubstituted or fluorinatedC₁₋₂alkoxy(C₁₋₃)alkyl, unsubstituted or fluorinated C₂₋₃alkenyl,unsubstituted or fluorinated C₁₋₂alkoxy(C₂₋₃)alkenyl, and C₂₋₃alkynyl,R11 is hydrogen, methoxy. fluoro, or chloro and R12, if present, ishydrogen or fluoro.

In one embodiment, the compounds have a structure selected from FormulaIII(a) to III(c)

wherein R4, R5, R6, R8, R10, R11 and R12 are as otherwise described forFormulae I and III herein,

wherein in Formula III(a), Q1 is S or O, and

wherein in Formula III(b), R13 and R14 are selected from the group ofhydrogen, methyl and fluoro and are preferably either both hydrogen orboth fluoro, and vwherein in Formula III(c), Q2 is S or O, preferably S,and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

In a preferred embodiment of the compounds of Formula III(a) to III(c),

R4 and R5 are both hydrogen,

R6 is selected from fluoro, chloro, bromo, mono-, di-, andtrifluoromethyl, methoxy and fluoromethoxy,

R8, if present, is hydrogen or fluoro, preferably hydrogen,

R10, if present, is selected from hydrogen and halogen, preferably fromhydrogen, fluoro and chloro,

R11 is selected from hydrogen, halogen, trifluoromethyl and cyano,preferably from fluoro and hydrogen,

R12 is selected from hydrogen, halogen and trifluoromethyl, preferablyfrom hydrogen and fluoro.

One embodiment refers to compounds of Formula Ild, Ile, IIla and IIIb

wherein R4 and R5 are both hydrogen,

R6 is selected from fluoro, chloro, bromo, mono-, di-, andtrifluoromethyl, and methoxy,

R10 is selected from hydrogen and halogen, preferably from hydrogen,fluoro and chloro,

R11 is selected from hydrogen, halogen, trifluoromethyl and cyano,preferably from fluoro and hydrogen,

R12 is selected from hydrogen, halogen and trifluoromethyl,

wherein in the compounds of Formula II(d) and III(a), Q1 is S or 0, and

wherein in Formula II(e) and III(b), R13 and R14 are selected fromhydrogen and fluoro and are preferably either both hydrogen or bothfluoro.

One embodiment refers to compounds of Formula Ilf and IIIc,

wherein R4 and R5 are both hydrogen,

R6 is selected from fluoro, chloro, bromo, methylsulfonyl, mono-, di-,and trifluoromethyl and phenyl,

R7, if present, is selected from hydrogen, methoxy, fluoro, andtrifluoromethyl,

R8 is selected from hydrogen and halogen, preferably from hydrogen andfluoro,

R11 is selected from hydrogen, halogen, trifluoromethyl and cyano, andis preferably hydrogen,

R12 is selected from hydrogen, halogen and trifluoromethyl, preferablyfrom fluoro and hydrogen,

Q2 is O or S, and is preferably S.

One embodiment relates to compounds of subformula IIla, IIIb, and IIIc,which are additionally substituted with a group R2, as depicted for thegeneral Formula III-2 above, thus leading to the respectivecorresponding compounds having subformula III-2a, III-2b, and III-2c,wherein R2 is selected from hydrogen, fluoro, chloro, bromo, iodo andmethoxy, and wherein R2 is preferably hydrogen or fluoro, andparticularly preferably hydrogen, and wherein the other residues are asdefined in the formula Illa,IIIb, and IIIc herein.

By way of example, if a compound of formula Ill-c also carries a R2group, the resulting compound of Formula III-2c is as follows:

Another aspect of the present invention relates to compounds having thegeneral formula VI, and pharmaceutically acceptable salts, solvates,isotopes and co-crystals thereof,

wherein X1, X2, R2, R4, R5, R6, R8, R9, R10 and R11 have the meaning asdescribed for the compounds of formula I-2, II-2, III-2, IV-2 or V-2hereinbefore, and wherein R2 is selected from hydrogen, fluoro, chloro,bromo, iodo and methoxy, preferably from hydrogen and fluoro; morepreferably, R2 is hydrogen.

One embodiment relates to a compound of Formula VI, wherein

X1 is C-R7 or N

X2 is NH, S or O, wherein if X1 is N, then X2 is preferably NH,

R2 is hydrogen or fluoro, preferably hydrogen,

R4 is hydrogen or fluoro,

R5 is selected from hydrogen, halogen, cyano, unsubstituted orfluorinated C₁₋₃ alkyl, unsubstituted or fluorinated C₁₋₃ alkoxy,unsubstituted or fluorinated C₁₋₃ alkylcarbonyl, unsubstituted orfluorinated C₁₋₃ alkylsulfinyl, and unsubstituted or fluorinated C₁₋₃alkylsulfonyl, wherein R5 is preferably selected from hydrogen, halogen,cyano, methyl, methoxy, fluoromethyl and fluoromethoxy, and is morepreferably selected from hydrogen, fluoro, chloro and bromo,

or R5 forms a ring together with R6 as described herein,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido,nitro, amino, C₁₋₃alkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, C₁₋₃alkoxy, C₃₋₆cycloalkyl, C₃₋₆ heterocycloalkyl, phenyl, C₅₋₆heteroaryl, C₃₋₆cycloalkyloxy, C₃₋₆ heterocycloalkyloxy, phenyloxy, C₅₋₆heteroaryloxy,C₁₋₃alkylsulfinyl, phenylsulfinyl, C₁₋₃alkylsulfonyl, phenylsulfonyl,benzylsulfonyl, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxycarbonyl, C₁₋₃alkylaminocarbonyl, di(C₁₋₃)alkylaminocarbonyl,C₃₋₆cycloalkyl(C₁₋₂)alkyl, heterocycloalkyl(C₁₋₂)alkyl,phenyl(C₁₋₂)alkyl, C₅₋₆ heteroaryl(C1-2)alkyl, C₃₋₆cycloalkyl(C₁₋₃)alkoxy, C₃₋₆ heterocycloalkyl(C₁₋₂)alkyloxy,phenyl(C₁₋₂)alkoxy C₅₋₆heteroaryl(C₁₋₂)alkoxy,phenyl(C₁₋₂)alkylsulfinyl, phenyl(C₁₋₂)alkylsulfonyl and wherein eachgroup in R6 can be unsubstituted or substituted with one or more groupsselected from fluoro, chloro, bromo, fluorinated or unsubstitutedC₁₋₃alkyl, fluorinated or unsubstituted C₁₋₃alkyloxy, hydroxy, andcyano,

or

(i) R6 forms together with R7 and the carbon atoms to which R6 and R7are attached, an unsubstituted or substituted phenyl, an unsubstitutedor substituted pyridyl, an unsubstituted or substituted cyclopentyl oran unsubstituted or substituted cyclohexyl,

wherein each substitution, if present, is selected from hydroxy,halogen, methyl or methoxy, wherein each methyl or methoxy can beunsubstituted or substituted with one or more substituents selected fromhalogen and methoxy,

or

(ii) R6 forms together with R5 and the carbon atoms to which R6 and R5are attached, a 1,3-dioxolane which may be unsubstituted or substitutedwith one or two substituents selected from fluorine and methyl,

R7, if present, is selected from hydrogen, fluoro, chloro, bromo, iodo,cyano, C₁₋₃alkyl, C₁₋₃alkoxy, C₂₋₃alkynyl, C₂₋₃alkenyl,C₁₋₃alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃alkylsulfinyl,C₁₋₃alkylsulfonyl, C₁₋₃alkylthio, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyloxy,C₃₋₆heterocycloalkyl, C₃₋₆heterocycloalkyloxy, phenyl, phenoxy,phenylsulfonyl, phenylsulfinyl, C₆₋₆heteroaryl, C₅₋₆heteroaryloxy,C₆₋₆heteroaryl(C₁₋₂)alkyl, and C₆₋₆heteroaryl(C₁₋₂)alkoxy,C₃₋₆cycloalkyl(C₁₋₂)alkyl, alkyl, C₃₋₆cycloalkyl(C₁₋₃)alkoxy, C₃₋₆heterocycloalkyloxy, C₃₋₆ heterocycloalkyl(C₁₋₂)alkyl,heterocycloalkyl(C₁₋₂)alkyloxy, phenyl(C₁₋₂)alkyl, phenyl(C₁₋₂)alkoxy,and wherein each group in R7 can be unsubstituted or substituted withone or more groups selected from fluoro, chloro, bromo, fluorinated orunsubstituted C₁₋₃alkyl, fluorinated or unsubstituted C₁₋₃alkyloxy,hydroxy, and cyano, or R7 forms a ring together with R6 as describedherein,

R8 is selected from hydrogen, optionally halogenated preferablyfluorinated or nsubstituted C₁₋₃alkyl, optionally halogenated preferablyfluorinated or unsubstitued C₁₋₃alkyloxy, cyano and halogen,

R9 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkyl,fluoro(C₁₋₃)alkyl, C₁₋₃alkoxy and fluoro(C₁₋₃)alkoxy, wherein R9 ispreferably hydrogen or fluoro,

R10 is selected from hydrogen, halogen, C₁₋₃alkyl, C₁₋₃alkoxy,C₂₋₃alkenyl, C₂₋₃alkynyl, cyano, C₁₋₃alkylcarbonyl, C₁₋₃alkoxycarbonyl,C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, C₁₋₃ alkylthio, C₃₋₆cycloalkyl,C₃₋₆cycloalkyloxy C₃₋₆heterocycloalkyl, C₃₋₆heterocycloalkyloxy, azido,pentafluorosulfanyl, nitro, C₁₋₃alkylaminocarbonyl, anddi(C₁₋₃)alkylaminocarbonyl, wherein each alkyl, alkenyl, alkynyl oralkoxy in R10 can be unsubstituted or substituted with one or moresubstituents selected from halogen, unsubstituted or halogenatedC₁₋₃alkoxy, unsubstituted or halogenated C₁₋₃alkylthio, unsubstituted orhalogenated C₁₋₃alkylcarbonyl, unsubstituted or halogenatedC₁₋₃alkyloxycarbonyl, unsubstituted or halogenatedC₁₋₃alkylaminocarbonyl, unsubstituted or halogenateddi(C₁₋₃)alkylaminocarbonyl, hydroxy, cyano, C₃₋₆cycloalkyl,C₃₋₆heterocycloalkyl, phenyl, and C₅₋₆heteroaryl, wherein anycycloalkyl, heterocycloalkyl, phenyl and heteroaryl may be unsubstitutedor substituted with one or more residues selected from halogen, hydroxy,hydroxymethyl, cyano, nitro, unsubstituted or halogenated C₁₋₃alkyl,unsubstituted or halogenated C₁₋₃alkoxy, unsubstituted or halogenatedC₁₋₃alkylcarbonyl and unsubstituted or halogenated C₁₋₃alkoxycarbonyl,and wherein any halogenated substituent in R10 is preferably fluorinatedand wherein R8 and R10 are preferably not hydrogen,

R11 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano,unsubstituted or fluorinated C₁₋₃alkyl, and unsubstituted or fluorinatedC₁₋₃alkyloxy, and is preferably selected from hydrogen, fluoro, chloro,methyl, fluoromethyl, methoxy and fluoromethoxy, and pharmaceuticallyacceptable salts, solvates, isotopes and co-crystals thereof.

One embodiment relates to a compound of formula VI, wherein

X1 is C-R7 or N,

X2 is NH, S or O, wherein X2 is preferably NH

R2 and R4 are both hydrogen,

R5 is selected from hydrogen, fluoro, chloro and bromo,

R6 is selected from hydrogen, fluoro, chloro, bromo, cyano, azido,nitro, C₁₋₃alkyl, C₁₋₃alkyloxy, cyclopropyl, cyclopropyloxy, oxetanyl,tetrahydrofuranyl, methylsulfonyl, methylsulfinyl, thienyl, pyridyl, andbenzyloxy, wherein each alkyl or alkoxy group in R6 can be unsubstitutedor substituted with one or more groups selected from fluoro, chloro,bromo, unsubstituted or fluorinated C₁₋₂alkyloxy and cyclopropyl andwherein each cyclopropyl, thienyl, pyridyl and phenyl group in R6 can besubstituted with one or more groups selected from halogen, methoxy,fluoromethoxy, methyl, fluoromethyl and cyano, or R6 forms together withR7 and the carbon atoms to which R6 and R7 are attached, anunsubstituted or substituted phenyl, an unsubstituted or substitutedpyridyl, an unsubstituted or substituted cyclopentyl or an unsubstitutedor substituted cyclohexyl, wherein each substitution of a ring formed byR6 and R7 is selected from hydroxy, halogen, cyano, methyl or methoxy,wherein each methyl or methoxy can be unsubstituted or fluorinated,

R7, if present, is selected from hydrogen, halogen, cyano, C₁₋₃alkyl,C₁₋₃alkoxy, methylsulfinyl and methylsulfonyl, wherein alkyl or alkoxygroup in R7 can be unsubstituted or substituted with one or more groupsselected from fluoro, chloro, cyano, and unsubstituted or fluorinatedC₁₋₂alkyloxy, or R7 forms a ring together with R6 as described herein,

R8 is selected from hydrogen, fluoro, chloro, unsubstituted orfluorinated methyl, and unsubstituted or fluorinated methoxy,

R9 is selected from hydrogen, fluoro, methyl, fluoromethyl, methoxy, andfluoromethoxy, and is preferably hydrogen,

R10 is selected from hydrogen, halogen, C₁₋₃alkyl, C₁₋₃alkyloxy,C₂₋₃alkenyl, C₂₋₃alkynyl, C₁₋₃ alkylcarbonyl, C₃₋₄cycloalkyl and cyano,wherein each alkyl, alkenyl, alkynyl or alkoxy can be unsubstituted orsubstituted with one or more substituents selected from fluoro, chloro,bromo, fluorinated or unsubstituted C₁₋₃alkyloxy, fluorinated orunsubstituted C₁₋₃alkylcarbonyl, fluorinated or unsubstitutedC₁₋₃alkoxycarbonyl, C₃₋₅cycloalkyl, C₃₋₅cycloalkyloxy,C₃₋₅heterocycloalkyl, C₃₋₅heterocycloalkyloxy, hydroxy and cyano,wherein any cycloalkyl, heterocycloalkyl, cycloalkyloxy andheterocycloalkyloxy may be unsubstituted or substituted with one or moreresidues selected from halogen, hydroxy, hydroxymethyl, cyano,fluorinated or unsubstituted methyl, fluorinated or unsubstitutedC₁₋₃alkyloxy, fluorinated or unsubstituted C₁₋₃alkyloxycarbonyl andfluorinated or unsubstituted C₁₋₃alkyloxy(C₁₋₃)alkyloxy,

R11 is selected from hydrogen, fluoro, chloro, bromo, unsubstituted orfluorinated C₁₋₃ alkyl, and unsubstituted or fluorinated C₁₋₃ alkyloxy,and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

In one preferred embodiment of the compounds of Formula VI, R6 is nothydrogen; in a more preferred embodiment at least one of, preferably twoof R8, R10 and R11 are also different from hydrogen. In one embodiment,R6 and R10 are both not hydrogen.

In one preferred embodiment of the present invention, in a compound ofFormula VI, either

(a) X1 is CR7 and X2 is NH, S or O, or

(b) X1 is N and X2 is NH,

Hence, preferred substructures of Formula VI are those of Formula VIa,VIb, VIc and VId as follows:

wherein any R2, R4, R5, R6, R7, if present, R8, R9, R10 and R11 are asdescribed as for compounds of formula 1-2, II-2, III-2, IV-2, V-2 and VIherein.

In one preferred embodiment of the invention, in the compounds offormula VI and VIa-d,

R2 is hydrogen or fluoro,

R4 is selected from hydrogen, methoxy and fluoro, and is preferablyhydrogen or fluoro, more preferably hydrogen,

R5 is selected from hydrogen, halogen, cyano, C₁₋₃alkoxy, C₁₋₃alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃alkylsulfinyl, andC₁₋₃alkylsulfonyl, wherein each alkyl or alkoxy may optionally besubstituted one or more times with a group selected from halogen, C₁₋₃alkoxy, halo(C₁₋₃)alkoxy, cyano, hydroxyl, and C₁₋₃ alkylamino, withpreferred optional substitutions of said alkyl and alkoxy groups beinghalogen and C₁₋₆ alkoxy, or R5 forms a ring together with R6 asdescribed herein,

R6 is selected from hydrogen, hydroxy, halogen, cyano, azido, nitro,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl,C₃₋₆ cycloalkenyl, C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl,phenyl, C₅₋₁₀heteroaryl preferably C₅₋₆heteroaryl, C₈₋₁₀ heterocyclyl,—ORx, —SRx, —SORx, SO₂Rx, -pentafluorosulfanyl , NRyRzz,—NRyCORx,—NRyCO₂Rx, —NRxCONRyRz, —CORx, —CO₂Rx,—CONRyRz, wherein eachalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, phenyl, heteroaryl or heterocyclylgroup in R6 can be unsubstituted or substituted with one or moresubstituents preferably selected from halogen, hydroxyl, oxo, cyano,azido, nitro, C₁₋₆ alkyl, C₁₋₆ alkoxy(C₁₋₃)alkyl , C₃₋₇ cycloalkyl, C₃₋₇heterocycloalkyl, phenyl, C₅₋₁₀ (preferably C₅₋₆) heteroaryl, ORx, —Rx,—SORx, SO₂Rx, -pentafluorosulfanyl, NRyRz, —NRyCORx,—NRyCO₂Rx, —CORx,—CO₂Rx,—CONRyRz, wherein Rx, Ry, Rz and Rzz are independently selectedfrom hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ cycloalkenyl, C₃₋₇cycloalkyl(C₁₋₆)alkyl, phenyl, phenyl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl,C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl, C₅₋₆ heteroaryl orheteroaryl(C1-6)alkyl, any of which groups can be unsubstituted orsubstituted with one or more substituents, or Ry and Rz, or Ry and Rzztogether with the amino atom to which they are both attached may form anaromatic or non aromatic, unsubstituted or substituted C₅₋₆ heterocycle,wherein Rzz is preferably different from hydrogen, or in the compoundsof formula VI, VIa, VIb or VIc R6 may form together with R5 or R7 andthe carbon atoms to which they are attached a 5 or 6 membered aromaticor non-aromatic ring which may optionally contain one or moreheteroatoms selected from S, O, and N, and wherein said ring can beunsubstituted or substituted with one or more substituents,

wherein preferably R6 forms together with R7 and the carbon atoms towhich R6 and R7 are attached, an unsubstituted or substituted phenyl,unsubstituted or substituted pyridyl, unsubstituted or substitutedcyclopentyl or unsubstituted or substituted cyclohexyl, wherein eachsubstitution, if present, is selected from halogen, hydroxy, cyano,C₁₋₃alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₃) alkyl, C₃₋₇heterocycloalkyl(C₁₋₃)alkyl, C₁₋₃alkoxy, and C₁₋₃alkoxy(C₁₋₃) alkyl,wherein each alkyl or alkoxy can be unsubstituted or substituted withone or more substituents selected from halogen and C₁₋₃alkoxy, or (ii)R6 forms together with R5 and the carbon atoms to which R6 and R5 areattached, a 1,3-dioxolane which may be unsubstituted or substituted withone or two substituents selected from fluoro and methyl, or

R7, if present, is selected from H, halogen, cyano, C₁₋₆ alkyl, C₁₋₆alkoxy, C₂₋₆ alkynyl, C₂₋₆ alkenyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₅alkylcarbonylamino, C₁₋₅ alkylaminocarbonyl,di(C₁₋₃)alkylaminocarbonyl, C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfinyl, C₃₋₇cycloalkyl, C₃₋₇ heterocycloalkyl, phenyl, C₅₋₆ heteroaryl, C₅₋₆heteroaryl(C₁₋₃)alkyl and C₅₋₆ heteroaryl(C₁₋₃)alkoxy, wherein eachalkyl, alkenyl, alkynyl or alkoxy group can be unsubstituted orsubstituted with one or more substituents selected from halogen,halo(C₁₋₆) alkoxy preferably fluro(C₁₋₃)alkoxy and C₁₋₆ alkoxy,

R8 is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, and halogen,wherein each alkyl or alkoxy can be unsubstituted or substituted withone or more substituents selected from halogen and optionallyfluorinated C₁₋₃alkoxy,

R9 is selected from hydrogen, halogen, cyano, azido, C₁₋₆ alkyl, C₁₋₆alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl and halogen, wherein each alkyl oralkoxy can be unsubstituted or substituted with one or more substituentsselected from halogen and C₁₋₃alkoxy,

R10 is selected from hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, cyano, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl,C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylthio,C₁₋₅alkylcarbonylamino, C₁₋₅ alkylaminocarbonyl,di(C₁₋₃)alkylaminocarbonyl, C₃₋₆cycloalkyl, hetero(C₃₋₆)cycloalkyl,azido, pentafluorosulfanyl, and nitro, wherein each alkyl, alkenyl,alkynyl or alkoxy can be unsubstituted or substituted with one or moresubstituents selected from halogen, C₁₋₆ alkoxy, halo(C₁₋₆)alkoxy,unsubstituted or fluorinated C₁₋₃ alkoxycarbonyl, unsubstituted orfluorinated C₁₋₃ alkylcarbonyl, C₁₋₆ alkylthio, unsubstituted orfluorinated C₁₋₃alkylcarbonylamino, unsubstituted or fluorinated C₁₋₃alkylaminocarbonyl, unsubstituted or fluorinateddi(C₁₋₃)alkylaminocarbonyl, unsubstituted or fluorinatedC₁₋₃alkylsulfonyl, unsubstituted or fluorinated C₁₋₃alkylsulfinyl,hydroxy, cyano, cyclo(C₃₋₆)alkyl, phenyl, and C₅₋₆heteroaryl, whereinany cycloalkyl, heterocycloalkyl, phenyl and heteroaryl may beunsubstituted or substituted with one or more residues selected fromhalogen, hydroxy, cyano, unsubstituted or fluorinated C₁₋₃ alkyl,unsubstituted or fluorinated C₁₋₃alkoxy, and unsubstituted orfluorinated C₁₋₃alkoxycarbonyl,

R11 is selected from hydrogen, halogen, cyano, azido, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylsulfonyl, andC₁₋₆alkylsulfinyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein each alkyl oralkoxy can be unsubstituted or substituted with one or more substituentsselected from halogen and C₁₋₃alkoxy,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

In one embodiment, in the compounds of Formula VI and VIa-d, at leastone of the group R5, R6 and R7, if present, and at least one, preferablytwo of the group R8, R10 and R11 are different from hydrogen, whereinmore preferably at least one substituent is selected from fluoro, chloroand bromo.

In one embodiment, in the compounds of Formula VI and VIa-d,

X1, if present, is N or CR7,

X2, if present, is NH, S or 0, wherein if X1 is N, then X2 is preferablyNH,

R2 is hydrogen or fluoro, preferably hydrogen,

R4 is hydrogen or fluoro, preferably hydrogen,

R5 is selected from hydrogen, halogen, cyano, C₁₋₂ alkyl, and C₁₋₂alkyloxy, wherein R5 is preferably hydrogen, methyl or halogen, or R5forms a ring together with R6 as described herein,

R6 is selected from hydrogen, halogen, cyano, nitro, amino, azido,C₁₋₃alkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, C₁₋₃alkyloxy, C₁₋₃ alkylcarbonyl,C₁₋₃ alkoxycarbonyl, C₁₋₃alkylcarbonylamino, C₁₋₃alkylaminocarbonyl,di(C₁₋₃)alkylaminocarbonyl, (C₁₋₃)alkylsulfinyl, (C₁₋₃)alkylsulfonyl,C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyloxy, C₃₋₆ cycloalkyl(C₁₋₂)alkyl,C₃₋₆cycloalkyl(C₁₋₃)alkoxy, C₃₋₆ heterocycloalkyl, C₃₋₆heterocycloalkyloxy, C₃₋₆ heterocycloalkyl(C₁₋₂)alkyl,heterocycloalkyl(C₁₋₂)alkyloxy, phenyl, phenyloxy, phenyl(C₁₋₂)alkyl,phenyl(C₁₋₂)alkoxy, phenylsulfonyl, phenylsulfinyl,phenyl(C₁₋₂)alkylsulfonyl, phenyl(C₁₋₂)alkylsulfinyl, C₅₋₆heteroaryl,C₅₋₆heteroaryloxy, C₅₋₆heteroaryl(C₁₋₂)alkyl, andC₅₋₆heteroaryl(C₁₋₂)alkoxy and wherein each group in R6 can beunsubstituted or substituted with one or more groups selected fromfluoro, chloro, bromo, fluorinated or unsubstituted C₁₋₃alkyl,fluorinated or unsubstituted C₁₋₃alkyloxy, hydroxy, and cyano,

or

-   -   (i) wherein in the compounds of formula VI, VIa, VIb or VIc R6        may form together with R7 and the carbon atoms to which R6 and        R7 are attached, an unsubstituted or substituted phenyl, an        unsubstituted or substituted pyridyl, an unsubstituted or        substituted cyclopentyl or an unsubstituted or substituted        cyclohexyl,        -   wherein each substitution, if present, is selected from            hydroxy, halogen, methyl or methoxy, wherein each methyl or            methoxy can be unsubstituted or substituted with one or more            substituents selected from halogen, preferably fluoro, and            methoxy,    -   or    -   (ii) R6 forms together with R5 and the carbon atoms to which R6        and R5 are attached, a 1,3-dioxolane which may be unsubstituted        or substituted with one or two substituents selected from fluoro        and methyl,

R7, if present, is selected from hydrogen, fluoro, chloro, bromo, iodo,cyano, azido, nitro, amino, C₁₋₃alkyl, C₂₋₃alkenyl, C₂₋₃alkynyl,C₁₋₃alkyloxy, C₁₋₃alkylcarbonyl, C₁₋₃ alkoxycarbonyl,C₁₋₃alkylcarbonylamino, C₁₋₃alkylaminocarbonyl, di(C₁₋₃)alkylaminocarbonyl, C₁₋₃alkylsulfinyl, C₁₋₃alkylsulfonyl, C₁₋₃alkylthio,C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyloxy, C₃₋₆ cycloalkyl(C₁₋₂)alkyl,C₃₋₆cycloalkyl(C₁₋₃)alkoxy, C₃₋₆ heterocycloalkyl, C₃₋₆heterocycloalkyloxy, C₃₋₆ heterocycloalkyl(C₁₋₂)alkyl,heterocycloalkyl(C₁₋₂)alkyloxy, phenyl, phenyloxy, phenyl(C₁₋₂)alkyl,phenyl(C₁₋₂)alkoxy, phenylsulfonyl, phenylsulfinyl, C₅₋₆heteroaryl,C₅₋₆heteroaryloxy, C₅₋₆heteroaryl(C₁₋₂)alkyl, andC₅₋₆heteroaryl(C₁₋₂)alkoxy and wherein each group in R7 can beunsubstituted or substituted with one or more groups selected fromfluoro, chloro, bromo, fluorinated or unsubstituted C₁₋₃alkyl,fluorinated or unsubstituted C₁₋₃alkyloxy, hydroxy, and cyano, or R7forms a ring together with R6 as described herein,

R8 is selected from hydrogen, halogen, cyano, optionally halogenatedC₁₋₃alkyloxy, optionally halogenated C₁₋₃alkyl, optionally halogenated(C₁₋₃)alkylsulfinyl, optionally halogenated (C₁₋₃)alkylsulfonyl andoptionally halogenated (C₁₋₃)alkylthio,

R9 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkyloxy,fluoro(C₁₋₃)alkoxy, C₁₋₃ alkyl, and fluoro(C₁₋₃)alkyl, and is preferablyhydrogen,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano,nitro, amino, azido, pentafluorosulfanyl, C₁₋₃alkyl, C₂₋₃alkenyl,C₂₋₃alkynyl, C₁₋₃alkyloxy, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxycarbonyl,C₁₋₃alkylaminocarbonyl, di(C₁₋₃)alkylaminocarbonyl, (C₁₋₃)alkylsulfinyl,(C₁₋₃) alkylsulfonyl, (C₁₋₃)alkylthio, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyloxy, C₃₋₆ cycloalkyl(C₁₋₂)alkyl, C₃₋₆ cycloalkyl(C₁₋₃)alkoxy,C₃₋₆ heterocycloalkyl, C₃₋₆ heterocycloalkyloxy, C₃₋₆heterocycloalkyl(C₁₋₂)alkyl, C₃₋₆ heterocycloalkyl(C₁₋₂)alkyloxy, andwherein each group in R10 can be unsubstituted or substituted with oneor more groups selected from fluoro, chloro, bromo, fluorinated orunsubstituted C₁₋₃alkyl, fluorinated or unsubstituted C₁₋₃alkyloxy,fluorinated or unsubstituted C₁₋₃alkoxycarbonyl, fluorinated orunsubstituted C₁₋₃alkylcarbonyl, C₁₋₃alkylaminocarbonyl,di(C₁₋₃)alkylaminocarbonyl, hydroxy, and cyano,

R11 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkyl,fluoro(C₁₋₃)alkyl, C₁₋₃alkyloxy, fluoro(C₁₋₃)alkoxy, unsubstituted orfluorinated C₁₋₃alkylcarbonyl, unsubstituted or fluorinated C₁₋₃alkoxycarbonyl, and cyano,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

In one preferred embodiment, R6 and R10 are both different from hydrogenand are independently selected from a group as further defined herein.

In one embodiment, in the compounds of Formula VI and VIa-d,

R2 and R4 are both hydrogen,

R5 is selected from hydrogen, fluoro, chloro and bromo,

R6 is selected from fluoro, chloro, bromo, azido, cyano, benzyloxy,methylsulfonyl, methylsulfinyl, C₁₋₃alkyl, C₁₋₃alkyloxy, cyclopropyl,cyclopropyloxy and cyclopropylmethoxy, wherein each alkyl, alkoxy andcyclopropyl group in R6 can be unsubstituted or substituted with one ormore groups selected from fluoro, chloro, bromo and unsubstituted orfluorinated C₁₋₂alkyloxy, wherein R6 is preferably selected from fluoro,chloro, bromo, fluorinated methyl, and unsubstituted or fluorinatedmethoxy, or in the compounds of formula VI, VIa, VIb or VIc, R6 may formtogether with R7 and the carbon atoms to which R6 and R7 are attached,an unsubstituted or substituted phenyl, an unsubstituted or substitutedpyridyl, an unsubstituted or substituted cyclopentyl or an unsubstitutedor substituted cyclohexyl, wherein each substitution in R7, if present,is selected from hydroxy, halogen, cyano, methyl or methoxy, whereineach methyl or methoxy can be unsubstituted or fluorinated and/orhydroxylated,

R7, if present, is selected from hydrogen, halogen, cyano, C₁₋₃alkyl,C₁₋₃alkyloxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyloxy, methylsulfinyl andmethylsulfonyl, wherein each alkyl, alkoxy or cycloalkyl group in R7 canbe unsubstituted or substituted with one or more groups selected fromfluoro, chloro, cyano and unsubstituted or fluorinated C₁₋₂alkyloxy, orR7 forms a ring together with R6 as described herein,

R8 is selected from hydrogen, fluoro, chloro, unsubstituted orfluorinated methoxy and unsubstituted or fluorinated methyl,

R9 is selected from hydrogen, fluoro, methyl and methoxy, and ispreferably hydrogen,

R10 is selected from hydrogen, halogen, cyano, C₁₋₃alkyl, C₂₋₃alkenyl,C₂₋₃alkynyl, C₁₋₃alkyloxy, C₃₋₄cycloalkyl, C₃₋₄cycloalkyloxy,C₃₋₄heterocycloalkyl, and C₃₋₄heterocycloalkyloxy, wherein each alkyl,alkenyl, alkynyl and alkyloxy group in R10 can be unsubstituted orsubstituted with one or more groups selected from fluoro, chloro, bromo,fluorinated or unsubstituted C₁₋₃alkyloxy, fluorinated or unsubstitutedC₁₋₃alkylcarbonyl, fluorinated or unsubstituted C₁₋₃alkoxycarbonyl,C₃₋₄cycloalkyl, C₃₋₄cycloalkyloxy, C₃₋₄heterocycloalkyl,C₃₋₄heterocycloalkyloxy, hydroxy, and cyano, and wherein each cycloalkyland heterocycloalkyl group in R10 can be substituted with a residueselected from fluoro, chloro, bromo, hydroxy, hydroxymethyl, fluorinatedor unsubstituted C₁₋₃alkyl, fluorinated or unsubstituted C₁₋₃alkyloxy,fluorinated or unsubstituted C₁₋₂alkyloxyC₁₋₂alkyloxy and fluorinated orunsubstituted C₁₋₃alkoxycarbonyl,

R11 is selected from hydrogen, fluoro, chloro, bromo, unsubstituted orfluorinated C₁₋₃ alkyl preferably fluoromethyl, and unsubstituted orfluorinated C₁₋₃alkyloxy preferably methoxy and fluoromethoxy, whereinR11 is preferably selected from hydrogen, fluoro, chloro, methoxy andfluoromethyl,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

In one preferred embodiment of the compounds of Formula VI, R2 ishydrogen.

In one preferred embodiment of the compounds of Formula VI and VIa-d, R4is hydrogen or fluoro, particularly preferably hydrogen.

In one preferred embodiment of the compounds of Formula VI and VIa-d, R5is selected from hydrogen, fluoro, chloro, bromo, iodo, andunsubstituted or fluorinated methyl. In a particularly preferredembodiment, R5 is selected from hydrogen, fluoro, chloro, bromo andmethyl, and particularly preferably from hydrogen, fluoro, chloro andbromo. In one preferred embodiment of the compounds of Formula VI andVIa-d, if R6 is not hydrogen, then R5 is hydrogen.

In one embodiment of the compounds of Formula VIa-c, in particular inthe compounds of Formula VIa, R6 forms a ring together with R7 and theC-atoms atoms to which R6 and R7 are attached, wherein the ring ispreferably selected from phenyl, pyridyl, cyclopentyl and cyclohexyl,each of which may be unsubstituted or substituted with one or moresubstituents selected from halogen, hydrogen, oxo, C₁₋₃ alkylC₁₋₃alkoxy, fluoro C₁₋₃alkoxy, fluoro C₁₋₃alkyl, amino, cyano,di(C₁₋₃alkyl)amino, acetyl, C₁₋₃alkylsulfonyl, C1-3 alkylsulfanyl,C₁₋₃alkylthio, and wherein the substitution is preferably selected fromfluoro, chloro, bromo, cyano, hydroxy, methyl, fluoromethyl, methoxy andfluoromethoxy. In a preferred embodiment, in the compounds of formulaVIa, R6 and R7 form a ring which, together with the anulated bicyclicring, give a tricyclic moiety selected from 1 H-benzo[g]indol-3-yl, 1H-pyrrolo[3,2-h]quinolin-3-yl,1,6,7,8-tetrahydrocyclopenta[g]indo1-3-yl, and6,7,8,9-tetrahydro-1H-benzo[g]indo1-3-yl. In one embodiment, if R6 andR7 form a pyridyl ring to give 1 H-pyrrolo[3,2-h]quinolin-3-yl, thetricycle may be further substituted with a substituent selected fromfluoro, chloro, bromo, hydroxy, methoxy, fluoromethyl and fluromethoxy,preferably at the 8-position to give, for example,8-hydroxy-1H-pyrrolo[3,2-h]guinoline,8-(difluoromethyl)-1H-pyrrolo[3,2-h]guinoline or 8-(trifluoromethoxy)-1H-pyrrolo[3,2-h]quinoline. In one embodiment of the compounds of FormulaVIa-c, in particular in the compounds of Formula VIa, R6 forms a ringtogether with R7 and the C-atoms atoms to which R6 and R7 are attached,wherein the ring is selected from phenyl, pyridyl, cyclopentyl andcyclohexyl, which are unsubstituted or substituted with one or moresubstituents selected from fluoro, chloro, fluoromethyl andfluoromethoxy, wherein, in one preferred embodiment, the ring isunsubstituted.

In one preferred embodiment of the compounds of Formula VIa-c, if R6 andR7 form an optionally substituted ring selected from phenyl, pyridyl,cyclopentyl and cyclohexyl, then R4 and R5 are preferably both hydrogen,R8 is hydrogen, halogen or unsubstituted or fluorinated methoxy,preferably fluoro or methoxy, R9 is hydrogen or fluoro preferablyhydrogen, R10 is selected from halogen, cyano, cyanomethyl, cyanoethyl,cyanomethoxy, nitro, azido, pentafluorosulfanyl, unsubstituted orfluorinated and/or hydroxylated, preferably unsubstituted or fluorinatedC₁₋₃ alkyl, unsubstituted or fluorinated and/or hydroxylated, preferablyunsubstituted or fluorinated C₁₋₃alkylcarbonyl, unsubstituted orfluorinated and/or hydroxylated, preferably unsubstituted or fluorinatedC₁₋₃alkoxy, unsubstituted or fluorinated C₂₋₃ alkenyl, C₂₋₃ alkynyl,unsubstituted or fluorinated and/or hydroxylated, preferablyunsubstituted or fluorinated C₁₋₂ alkoxy(C₁₋₃)alkyl, unsubstituted orfluorinated and/or hydroxylated, preferably unsubstituted or fluorinatedC₁₋₂ alkoxy(C₁₋₃) alkoxy, R11 is selected from hydrogen, fluoro, chloro,bromo, unsubstituted or fluorinated methoxy and unsubstituted orfluorinated methyl.

In one embodiment, in the compounds of formula VIa, R6 and R7 form apyridine and the tricyclic ring system formed is optionally substituted1 H-pyrrolo[3,2-h]quinolin-3-yl, preferably 8-substituted1H-pyrrolo[3,2-h]quinoline.

In one preferred embodiment of the compounds of Formula VIa, R6 and R7form an optionally substituted ring selected from phenyl, pyridyl (topreferably form optionally 8-substituted1H-pyrrolo[3,2-h]quinolin-3-yl), cyclopentyl and cyclohexyl, R4 and R5are both hydrogen, R8 is fluoro or unsubstituted or fluorinated methoxy,R9 is hydrogen or fluoro, preferably hydrogen, R10 is selected fromfluoro, chloro, bromo, iodo, cyano, cyanomethyl, cyanoethyl,cyanomethoxy, unsubstituted or fluorinated C₁₋₃ alkyl, unsubstituted orfluorinated C₁₋₃alkoxy, unsubstituted or fluorinated C₂₋₃ alkenyl, C₂₋₃alkynyl, unsubstituted or fluorinated C₁₋₂ alkoxy(C₁₋₃)alkyl andunsubstituted or fluorinated C₁₋₂ alkoxy(C₁₋₃)alkoxy, R11 is selectedfrom hydrogen, fluoro, chloro, bromo, unsubstituted or fluorinatedmethoxy and unsubstituted or fluorinated methyl.

In one preferred embodiment of the compounds of Formula VI and VIa-d, R6is selected from fluoro, chloro, bromo, iodo, cyano, azido, amino,nitro, C₁₋₃alkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, C₁₋₃alkyloxy,C₁₋₃alkylcarbonylamino, C₁₋₃alkylaminocarbonyl, di(C₁₋₃)alkylaminocarbonyl, (C₁₋₃)alkylsulfinyl, (C₁₋₃)alkylsulfonyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyloxy, C₃₋₆ cycloalkyl(C₁₋₂)alkyl, C₃₋₆cycloalkyl(C₁₋₃)alkoxy, C₃₋₆ heterocycloalkyl, C₃₋₆ heterocycloalkyloxy,C₃₋₆ heterocycloalkyl(C₁₋₂)alkyl, heterocycloalkyl(C₁₋₂)alkyloxy,phenyl, phenyloxy, phenyl(C₁₋₂)alkyl, phenyl(C₁₋₂)alkoxy,phenylsulfonyl, benzylsulfonyl, phenylsulfinyl, benzylsulfinyl,C₅₋₆heteroaryl, C₅₋₆heteroaryloxy, C₅₋₆heteroaryl(C₁₋₂)alkyl, andC₅₋₆heteroaryl(C₁₋₂)alkoxy and wherein each group in R6 can beunsubstituted or substituted with one or more groups selected fromfluoro, chloro, bromo, fluorinated or unsubstituted C₁₋₂alkyl,fluorinated or unsubstituted C₁₋₂alkoxy, hydroxy, and cyano.

In one preferred embodiment of the compounds of Formula VI and VIa-d, R6is selected from fluoro, chloro, bromo, cyano, cyanomethyl,cyanomethoxy, nitro, azido, cyclopropyl, cyclopropyloxy,cycopropylmethoxy, unsubstituted or substituted C₁₋₃alkyl, unsubstitutedor substituted C₁₋₃alkyloxy, methylsulfinyl, methylsulfonyl, pyridyl,optionally halogenated thienyl, and benzyloxy, wherein each substitutionin R6 is selected from halo, methoxy and fluoromethoxy, and ispreferably fluoro. In one preferred embodiment, R6 is selected fromchloro, bromo, azido, cyano, cyclopropyl, methylsulfinyl,methylsulfonyl, mono-, di- and trifluoromethyl, methoxy, mono-, di- andtrifluoromethoxy, and mono-, di- and trifluoroethoxy. In a particularlypreferred embodiment, R6 is selected from fluoro, chloro, bromo,methoxy, fluoromethoxy, fluoroethoxy and fluoromethyl, and mostpreferably from fluoro, chloro, bromo and methoxy.

In one preferred embodiment of the compounds of Formula VIa-c, R7 isselected from hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro,C₁₋₃alkyl, C₁₋₃alkyloxy, C₁₋₃alkylsulfinyl, C₁₋₃alkylsulfonyl,C₁₋₃alkylthio, C₃₋₆cycloalkyl, C₃₋₆cycloalkyloxy, C₃₋₆heterocycloalkyl,C₃₋₆heterocycloalkyloxy, phenyl, phenyloxy, phenyl(C₁₋₂)alkyl,phenyl(C₁₋₂)alkoxy, phenylsulfonyl, phenylsulfinyl, C₅₋₆heteroaryl,C₅₋₆heteroaryloxy, C₅₋₆heteroaryl(C₁₋₂)alkyl, andC₅₋₆heteroaryl(C₁₋₂)alkoxy, wherein each group in R7 can beunsubstituted or substituted with one or more residues selected fromfluoro, chloro, bromo, fluorinated or unsubstituted methyl, fluorinatedor unsubstituted C₁₋₃alkyloxy, hydroxy, and cyano, and wherein theC₅₋₆heteroaryl is preferably selected from pyridyl, oxazol and isoxazol,each of which may be substituted as described above. In one preferredembodiment, R7 is selected from hydrogen, fluoro, chloro, bromo, methyl,fluoromethyl, methoxy, fluoromethoxy, fluoroethoxy, methylsulfinyl,methylsulfonyl and optionally substituted isoxazol. In one preferredembodiment, R7 is selected from hydrogen, fluoro, chloro, bromo, methyl,fluoromethyl, methoxy, fluoromethoxy and methylsulfonyl.

In a preferred embodiment, in the compounds of Formula VI and VIa-d, R8is selected from hydrogen, halogen, cyano, unsubstituted or fluorinatedC₁₋₃ alkyl and unsubstituted or fluorinated C₁₋₃alkyloxy, preferablyfrom fluoro, chloro, bromo, methyl, fluoromethyl, methoxy andfluoromethoxy. In one preferred embodiment, R8 is selected from fluoro,methoxy and fluoromethoxy, and in a particularly preferred embodiment,R8 is fluoro or methoxy.

In one preferred embodiment, in the compounds of Formula VI and VIa-d,R9 is selected from hydrogen, fluoro, chloro, methyl, fluoromethyl,methoxy and fluoromethoxy. In one preferred embodiment, R9 is selectedfrom hydrogen, fluoro, methoxy and fluoromethoxy, and is more preferablyhydrogen or fluoro and particularly preferably hydrogen,

In one embodiment, in the compounds of Formula VI and VIa-d, R10 isselected from hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro,amino, azido, pentafluorosulfanyl, C₁₋₃alkyl, C₂₋₃alkenyl, C₂₋₃alkynyl,C₁₋₃alkyloxy, C₁₋₃alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃alkylcarbonylamino, C₁₋₃alkylaminocarbonyl, di(C₁₋₃)alkylaminocarbonyl,(C₁₋₃)alkylsulfinyl, (C₁₋₃)alkylsulfonyl, (C₁₋₃)alkylthio, C₃₋₄cycloalkyl, C₃₋₄ cycloalkyloxy, C₃₋₄ heterocycloalkyl, C₃₋₄heterocycloalkyloxy, C₃₋₄ heterocycloalkyl(C₁₋₂ )alkyl,C₃₋₄heterocycloalkyl(C₁₋₂)alkoxy, C₅₋₆heteroaryl(C₁₋₂)alkyl, andC₅₋₆heteroaryl(C₁₋₂)alkoxy and wherein each alkyl, alkenyl, alkynyl andalkoxy group in R10 can be unsubstituted or substituted with one or moregroups selected from fluoro, chloro, bromo, fluorinated or unsubstitutedC₁₋₃alkyloxy, C₁₋₃alkyloxycarbonyl, phenyl, phenyloxy, C₃₋₆ cycloalkyl,C₃₋₆ cycloalkyloxy, C₃₋₆ heterocycloalkyl, C₃₋₆ heterocycloalkyloxy,hydroxy, and cyano, and wherein each cyclic group in R10 can beunsubstituted or substituted with one or more residues selected fromfluoro, chloro, bromo, fluorinated or unsubstituted C₁₋₃alkyl,fluorinated or unsubstituted C₁₋₃alkyloxy, fluorinated or unsubstitutedC₁₋₃alkyloxycarbonyl, hydroxy, hydroxymethyl, and cyano.

In one embodiment, in the compounds of Formula VI and VIa-d, R10 isselected from hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro,amino, azido, pentafluorosulfanyl, C₁₋₃alkyl, C₂₋₃alkenyl, C₂₋₃alkynyl,C₁₋₃alkyloxy, C₁₋₃alkylcarbonyl, C₁₋₃alkoxycarbonyl, (C₁₋₃)alkylsulfinyl, (C₁₋₃)alkylsulfonyl, (C₁₋₃)alkylthio,C₁₋₃alkyloxycyclopropyl and C₁₋₃alkyloxycarbonylcyclopropyl, whereineach alkyl, alkoxy, alkenyl and alkynyl group in R10 can beunsubstituted or substituted with one or more groups selected fromfluoro, chloro, bromo, fluorinated or unsubstituted C₁₋₃alkyl,fluorinated or unsubstituted C₁₋₃alkyloxy, fluorinated or unsubstitutedC₁₋₃alkyloxycarbonyl, C₃₋₆ cycloalkyl and cyano.

In one preferred embodiment, R10 is selected from hydrogen, fluoro,chloro, bromo, iodo, cyano, cyanomethyl, cyanoethyl, cyanomethoxy,cyanoethoxy, nitro, azido, pentafluorosulfanyl, C₁₋₃alkyl, C₂₋₃alkenyl,C₂₋₃alkynyl, C₁₋₃alkyloxy, C₁₋₂ alkylcarbonyl and substitutedcyclopropyl, wherein each group in R10 can be unsubstituted orsubstituted with one or more groups selected from fluoro, unsubstitutedor fluorinated and/or hydroxylated, preferably unsubstituted orfluorinated C₁₋₂ alkyloxy, unsubstituted or fluorinated and/orhydroxylated, preferably unsubstituted or fluorinatedC₁₋₂alkyloxycarbonyl, unsubstituted or substituted cyclopropyl andhydroxy, provided that any substitution of cycopropyl is selected fromthe group of halogen, cyano, hydroxymethyl, optionally fluorinatedC₁₋₂alkoxy and optionally fluorinated C₁₋₂alkoxycarbonyl.

In one preferred embodiment, in the compound of the present invention,including but not limited to the compounds of Formula VI and VIa-d, R10is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano,cyanomethyl, cyanoethyl, cyanomethoxy, cyanoethoxy, nitro, azido,pentafluorosulfanyl, methyl, ethyl, propyl, fluoromethyl, fluoroethyl,fluoropropyl, methoxymethyl, fluoromethoxymethyl, methoxyethyl,fluoromethoxyethyl, methoxypropyl, fluoromethoxypropyl, ethoxymethyl,fluoroethoxymethyl, ethoxyethyl, fluoroethoxyethyl, propoxymethyl,fluoropropoxymethyl, methoxy, ethoxy, propoxy, fluoromethoxy,fluoroethoxy, fluoropropoxy, methoxymethoxy, fluoromethoxymethoxy,methoxyethoxy, fluoromethoxyethoxy, methoxypropoxy,fluoromethoxypropoxy, ethoxymethoxy, fluoroethoxymethoxy, ethoxyethoxy,fluoroethoxyethoxy, propoxymethoxy, fluoropropoxymethoxy, ethenyl,propenyl, fluoroethenyl, fluoropropenyl, methoxyethenyl,fluoromethoxyethenyl, methoxypropenyl, fluoromethoxypropenyl,ethoxyethenyl, fluoroethoxyethenyl, ethynyl, propynyl, methoxyethynyl,fluoromethoxyethynyl, methoxypropynyl, fluoromethoxypropynyl andcyclopropylmethoxy, wherein in one embodiment, each group in R10 may befurther suitably substituted with hydroxy.

In one preferred embodiment, R10 is a cyclic group selected fromC₃₋₅cycloalkyl, C₃₋₅cycloalkyloxy, C₃₋₅cycloalkyl(C₁₋₃)alkyl preferablycycloalkylmethyl, C₃₋₅cycloalkyl(C₁₋₃) alkoxy preferablycycloalkylmethoxy, C₃₋₅heterocycloalkyl, C₃₋₅heterocycloalkyloxy,C₃₋₅heterocycloalkyl(C₁₋₃)alkyl preferably heterocycloalkylmethyl, andC₃₋₅heterocycloalkyl(C₁₋₃alkoxy preferably heterocycloalkylmethoxy,wherein each cyclic group may be unsubstituted or substituted with oneor more substituents selected from halogen preferably fluoro, cyano,hydroxymethyl, optionally fluorinated C₁₋₃alkoxy, optionally fluorinatedC₁₋₂alkoxy(C₁₋₂)alkyl, optionally fluorinated C₁₋₂alkoxy(C₁₋₂)alkoxy,and optionally fluorinated C₁₋₂alkoxycarbonyl. In one preferredembodiment, the substitution is preferably selected from fluoro, cyanoand optionally fluorinated C₁₋₃alkoxy, wherein the cyclic group ispreferably cyclopropyl.

In one preferred embodiment, in the compound of the present invention,including but not limited to the compounds of formula VI and VIa-d, R10is selected from fluoro, chloro, bromo, iodo, cyano, cyanomethyl,cyanoethyl, cyanomethoxy, cyanoethoxy, pentafluorosulfanyl, methyl,ethyl, propyl, butyl, fluoromethyl, fluoroethyl, fluoropropyl,methoxymethyl, fluoromethoxymethyl, methoxyethyl, fluoromethoxyethyl,methoxypropyl, fluoromethoxypropyl, ethoxymethyl, fluoroethoxymethyl,ethoxyethyl, fluoroethoxyethyl, methoxy, ethoxy, propoxy, butyloxy,fluoromethoxy, fluoroethoxy, fluoropropoxy, methoxymethoxy,fluoromethoxymethoxy, methoxyethoxy, fluoromethoxyethoxy,methoxypropoxy, fluoromethoxypropoxy, ethoxymethoxy,fluoroethoxymethoxy, ethoxyethoxy, fluoroethoxyethoxy, ethenyl,propenyl, fluoroethenyl, fluoropropenyl, methoxyethenyl,fluoromethoxyethenyl, methoxypropenyl, fluoromethoxypropenyl,ethoxyethenyl, fluoroethoxyethenyl, ethynyl, propynyl,ethoxycyclopropyl, ethoxycarbonylcyclopropyl and cyclopropylmethoxy.

In one preferred embodiment, in the compound of the present invention,including but not limited to the compounds of formula VI and VIa-d, R10is selected from fluoro, chloro, bromo, cyano, cyanomethyl, cyanoethyl,methyl, mono-, di-, and trifluoromethyl, ethyl, mono-, di-, andtrifluoroethyl, propyl, mono-, di-, and trifluoropropyl, methoxy, mono-,di-, and trifluoromethoxy, ethoxy, mono-, di-, and trifluoroethoxy,propyloxy, mono-, di-, and trifluoropropyloxy, methoxymethyl, mono-,di-, and trifluoromethoxymethyl, methoxyethyl, mono-, di-, andtrifluoromethoxyethyl, methoxypropyl, mono-, di-, andtrifluoromethoxypropyl, methoxymethoxy, mono-, di-, andtrifluoromethoxymethoxy, methoxyethoxy, mono-, di-, andtrifluoromethoxyethoxy, methoxypropyloxy, mono-, di-, andtrifluoromethoxypropyloxy ethoxymethoxy, mono-, di-, andtrifluoroethoxymethoxy, methoxypropenyl, and mono-, di-, andtrifluoromethoxypropenyl.

In one preferred embodiment, R10 is selected from fluoro, chloro, bromo,iodo, cyano, cyanomethyl, cyanoethyl, cyanomethoxy, cyanoethoxy,unsubstituted or fluorinated C₁₋₃alkyl, unsubstituted or fluorinatedC₁₋₃alkoxy, unsubstituted or fluorinated C₁₋₂alkoxy(C₁₋₃) alkyl,unsubstituted or fluorinated C₁₋₂alkoxy(C₁₋₃)alkoxy, and unsubstitutedor fluorinated C₁₋₂alkoxy(C₂₋₃)alkenyl.

In one preferred embodiment, R10 is selected from halogen, C₁₋₄aalkoxy,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₃₋₆cycloalkyl preferablyC₃₋₄cycloalkyl, C₃₋₆cycloalkyloxy preferably C₃₋₄cycloalkyloxy,C₃₋₆heterocycloalkyl preferably C₃₋₄heterocycloalkyl, andC₃₋₆heterocycloalkyloxy preferably C₃₋₄cheterocycloalkyloxy, each ofwhich can be optionally substituted with a residue selected from cyano,fluoro and unsubstituted or fluorinated C₁₋₃alkoxy.

In one embodiment, in the compounds of formula VI and VIa-d, R11 isselected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyl,fluoro(C₁₋₃)alkyl, C₁₋₃ alkyloxy, fluoro(C₁₋₃) alkoxy, unsubstituted orfluorinated C₁₋₃alkylcarbonyl, and cyano. In a preferred embodiment, R11is selected from hydrogen, fluoro, chloro, methyl, fluoromethyl,methoxy, fluoromethoxy and cyano, more preferably from hydrogen, fluoro,floromethyl, methoxy and fluoromethoxy.

In one preferred embodiment, in the compounds of Formula VI and VIa-d,

R2, R4, R5 and R9 are all hydrogen,

R6 is selected from halogen, cyano, C₁₋₃alkoxy, C₁₋₃alkyl,C₃₋₆cycloalkyl preferably C₃₋₄acycloalkyl, C₃₋₆cycloalkyloxy preferablyC₃₋₄cycloalkyloxy, C₃₋₆heterocycloalkyl preferably C₃₋₄heterocycloalkyl,and C₃₋₆heterocycloalkyloxy preferably C₃₋₄heterocycloalkyloxy, each ofwhich can be optionally substituted with a residue selected from fluoroand unsubstituted or fluorinated C₁₋₃alkoxy,

R7 is selected from hydrogen, halogen, cyano, C₁₋₃alkoxy, C₁₋₃alkyl,C₃₋₆cycloalkyl preferably C₃₋₄cycloalkyl, C₃₋₆cycloalkyloxy preferablyC₃₋₄cycloalkyloxy, C₃₋₆heterocycloalkyl preferably C₃₋₄heterocycloalkyl,and C₃₋₆heterocycloalkyloxy preferably C₃₋₄heterocycloalkyloxy, each ofwhich can be optionally substituted with a residue selected from fluoroand unsubstituted or fluorinated C₁₋₃alkoxy,

R8 is selected from fluoro, methoxy and fluoromethoxy, preferably fromfluoro and methoxy,

R10 is selected from halogen, C₁₋₄aalkoxy, C₁₋₄aalkyl, C₂₋₃alkenylC₂₋₃alkynyl, C₃₋₆cycloalkyl preferably C₃₋₄cycloalkyl, C₃₋₆cycloalkyloxypreferably C₃₋₄cycloalkyloxy, C₃₋₆heterocycloalkyl preferablyC₃₋₄heterocycloalkyl, and C₃₋₆heterocycloalkyloxy preferablyC₃₋₄heterocycloalkyloxy, each of which can be optionally substitutedwith a residue selected from fluoro, cyano and unsubstituted orfluorinated C₁₋₃alkoxy, and

R11 is selected from hydrogen, fluoro, methoxy and fluoromethoxy,preferably from fluoro and methoxy.

In a preferred embodiment, in the compounds of formula VI and VIa-d,

R2 is hydrogen,

R4 is hydrogen or fluoro, more preferably hydrogen;

R5 is selected from hydrogen, fluoro, chloro and bromo;

R6 is selected from fluoro, chloro, bromo, azido, cyclopropyl,cyclopropyloxy, cycopropylmethoxy, unsubstituted or fluorinatedC₁₋₃alkyl, unsubstituted or fluorinated C1-₃alkyloxy, methylsulfinyl,methylsulfonyl, pyridyl, optionally halogenated thienyl and benzyloxy;

R7, if present, is selected from hydrogen, fluoro, chloro, bromo,methyl, fluoromethyl, methoxy, fluoromethoxy, fluoroethoxy,methylsulfinyl, and methylsulfonyl;

R8 is selected from hydrogen, fluoro, chloro, bromo, methyl,fluoromethyl, methoxy and fluoromethoxy;

R9 is selected from hydrogen, fluoro, chloro, methyl, fluromethyl,methoxy and fluoromethoxy, and is preferably hydrogen,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano,nitro, azido, pentafluorosulfanyl, C₁₋₃alkyl, C₂₋₃alkenyl, C₂₋₃alkynyl,C₁₋₃alkyloxy, C₁₋₃alkylcarbonyl, C₁₋₃alkoxycarbonyl and cyclopropyl,wherein the cyclopropyl is optionally substituted with a residueselected from cyano, C₁₋₂alkoxy, fluoro(C₁₋₂)alkoxy,C₁₋₂alkoxy(C₁₋₂)alkoxy, fluoro(C₁₋₂)alkoxy(C₁₋₂)alkoxy,C₁₋₂alkoxycarbonyl and fluoro(C₁₋₂)alkoxycarbonyl, and wherein eachalkyl, alkoxy, alkenyl and alkynyl group in R10 can be unsubstituted orsubstituted with one or more groups selected from halogen, fluorinatedor unsubstituted C₁₋₂alkyloxy, cyano, cyclopropyl and hydroxy, whereinsuch substitution is preferably selected from fluoro, fluorinated orunsubstituted C₁₋₂alkyloxy and cyano;

and R11 is selected from hydrogen, fluoro, chloro, methyl, fluoromethyl,methoxy, fluoromethoxy and cyano,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

In one preferred embodiment, in the compounds of formula VI and VIa-d,R2, if present, is hydrogen, R4 is hydrogen or fluoro, more preferablyhydrogen; R5 is selected from hydrogen, fluoro, chloro and bromo and ispreferably hydrogen; R6 is selected from fluoro, chloro, bromo, azido,methylsulfinyl, methylsulfonyl, methyl, mono-, di- and trifluoromethyl,methoxy, mono-, di- and trifluoromethoxy, and mono-, di- andtrifluoroethoxy; R7, if present, is selected from hydrogen, fluoro,chloro, bromo, methyl, fluoromethyl, methoxy, fluoromethoxy,fluoroethoxy, methylsulfinyl and methylsulfonyl, R8 is selected fromhydrogen, fluoro, chloro, bromo, methyl, fluoromethyl, methoxy andfluoromethoxy and is preferably fluoro or methoxy; R9 is selected fromhydrogen, fluoro, methoxy and fluoromethoxy, and is preferably hydrogen;R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano,cyanomethyl, cyanoethyl, cyanomethoxy, cyanoethoxy, unsubstituted orfluorinated C₁₋₃alkyl, unsubstituted or fluorinated C₁₋₃alkyloxy,unsubstituted or fluorinated C₁₋₂alkyloxy(C₁₋₃)alkyl, unsubstituted orfluorinated C₁₋₂alkyloxy(C₁₋₃)alkyloxy, unsubstituted or fluorinatedC₁₋₂ alkyloxy(C₂₋₃)alkenyl, cyclopropyl, cyclopropyloxy andcyclopropylmethoxy, wherein any cyclopropyl moiety is optionallysubstituted with a residue selected from fluoro, cyano, C₁₋₂alkoxy,fluoro(C₁₋₂)alkoxy, C₁₋₂alkoxy(C₁₋₂)alkoxy,fluoro(C₁₋₂)alkoxy(C₁₋₂)alkoxy, C₁₋₂alkoxycarbonyl,fluoro(C₁₋₂)alkoxycarbonyl; and R11 is selected from hydrogen, fluoro,chloro, methyl, fluoromethyl, methoxy and fluoromethoxy, whereinpreferably at least one, preferably two and more preferably allsubstituents in R8, R10 and R11 are different from hydrogen, and whereinin one particularly preferred embodiment R8 and R11 are bothindependently selected from fluoro and methoxy.

Another embodiment relates to compounds of Formula VI and VIa-d, whereinR2, if present, is hydrogen, R4 and R5 are both hydrogen, R6 is selectedfrom fluoro, chloro, bromo, methylsulfinyl, fluoromethyl, methoxy andfluoromethoxy, R7 is selected from hydrogen, fluoro, chloro, bromo,unsubstituted or fluorinated C₁₋₂alkyl, unsubstituted or fluorinatedC₁₋₂alkoxy, methylsulfinyl, and methylsulfonyl, R8 is selected fromhydrogen, fluoro, chloro methoxy and fluoromethoxy, R9 is hydrogen,methoxy or fluoro, preferably hydrogen, R10 is selected from fluoro,chloro, bromo, iodo, cyano, cyanomethyl, cyanoethyl, unsubstituted orfluorinated and/or hydroxylated C₁₋₃alkyl, unsubstituted or fluorinatedand/or hydroxylated C₁₋₃alkoxy, unsubstituted or fluorinated and/orhydroxylated C₁₋₂alkoxy(C₁₋₃)alkyl, unsubstituted or fluorinated and/orhydroxylated C₁₋₃2alkoxy(C₁₋₃)alkoxy, unsubstituted or fluorinatedand/or hydroxylated C₁₋₂alkoxy(C₂₋₃) alkenyl and unsubstituted orfluorinated C₁₋₂alkoxycarbonylcyclopropyl, and is preferably selectedfrom fluoro, chloro, bromo, iodo, cyano, cyanomethyl, cyanoethyl,unsubstituted or fluorinated C₁₋₃alkyl, unsubstituted or fluorinatedC₁₋₃alkoxy, unsubstituted or fluorinated C₁₋₂alkoxy(C₁₋₃)alkyl,unsubstituted or fluorinated C₁₋₂alkoxy(C₁₋₃)alkoxy, unsubstituted orfluorinated C₁₋₂alkoxy(C₂₋₃)alkenyl, unsubstituted or fluorinatedC₁₋₂alkoxycarbonylcyclopropyl and unsubstituted or fluorinatedC₁₋₃alkoxycyclopropyl, and

R11 is selected from hydrogen, fluoro, chloro, fluoromethyl, methoxy,and fluoromethoxy, wherein in a particular preferably embodiment, atleast one, more preferably both of R8 and R11 are different fromhydrogen.

A further embodiment relates to compounds of Formula VI and VIa-d,wherein

R2, R4 and R9 are all hydrogen,

R5 is hydrogen, fluoro, chloro or bromo, and is preferably hydrogen,

R6 is selected from fluoro, chloro, bromo, methoxy, fluoromethoxy,fluoromethyl and azido,

or in the compounds of formula VI, VIa, VIb or VIc R6 may form togetherwith R7 and the carbon atoms to which R6 and R7 are attached, a ringselected from phenyl, pyridyl, cyclohexyl and cyclopentyl, each of whichmay be unsubstituted or substituted with one or

two substituents selected from fluoro, chloro, hydroxy, cyano, methoxy,fluoromethoxy and fluoromethyl,

R7 is selected from hydrogen, fluoro, chloro, bromo, unsubstituted orfluorinated methyl, unsubstituted or fluorinated methoxy andmethylsulfinyl,

R8 is selected from fluoro, chloro, methoxy and fluoromethoxy,

R10 is selected from fluoro, chloro, bromo, iodo, cyano, cyanomethyl,cyanoethyl, cyanomethoxy, unsubstituted or fluorinated C₁₋₃alkyl,unsubstituted or fluorinated C₁₋₃alkoxy, unsubstituted or fluorinatedC₁₋₂alkoxy(C₁₋₃)alkyl, unsubstituted or fluorinatedC₁₋₂alkoxy(C₁₋₃)alkoxy, and unsubstituted or fluorinatedC₁₋₂alkoxy(C₂₋₃)alkenyl, wherein R10 is preferably selected from fluoro,chloro, bromo, cyanomethyl, cyanoethyl, unsubstituted or fluorinatedC₁₋₃alkyl, unsubstituted or fluorinated C₁₋₃alkoxy, unsubstituted orfluorinated C₁₋₂alkoxy(C₁₋₃)alkyl, unsubstituted or fluorinatedC₁₋₂alkoxy(C₁₋₃)alkoxy, unsubstituted or fluorinated C₁₋₂alkoxy(C₂₋₃)alkenyl, unsubstituted or fluorinatedC₁₋₃alkoxycycylopropyl, unsubstituted or fluorinatedC₁₋₃alkoxycarbonylcyclopropyl and unsubstituted or fluorinated C₁₋₂alkoxy(C₁₋₂ )alkoxycycylopropyl,

R11 is selected from hydrogen, fluoro, chloro, methyl, fluoromethyl,fluoromethoxy and methoxy,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

In one preferred embodiment, in the compounds of Formula VI and VIa-d,R6 and R10 are different from hydrogen and are independently selectedfrom a group as further defined herein.

In one preferred embodiment, in the compounds of Formula VI and VIa-d,R6, R8 and R10 are all different from hydrogen and are independentlyselected from a group as further defined herein

In one preferred embodiment, in the compounds of Formula VI and VIa-d,R6, R8, R10 and R11 are all different from hydrogen and areindependently selected from a group as further defined herein.

In one embodiment, in the compounds of Formula VI and VIa-c, R7 is nothydrogen.

In one preferred embodiment of the compounds of Formula VI and VIa-d,R6, R8 and at least one of R10 and R11 are all different from hydrogen,and are independently selected from a group as further defined herein

In one embodiment, in the compounds of Formula VI and VIa, R6 and R7form a ring selected from phenyl, pyridyl, cyclopentyl and cyclohexyl togive the formula Vle to Vlg below:

wherein

m is 0 or 1,

n is any number from 0 to 4, preferably from 0 to 2, more preferably 0or 1,

p is any number from 0 to 3, preferably from 0 to 2, more preferably 0or 1,

Y is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano,hydroxy, methyl and methoxy, wherein the methoxy and methyl group areoptionally substituted with one or more substituents selected fromfluoro, chloro, bromo, hydroxy, methoxy and fluoromethoxy,

R2 and R4 are both hydrogen,

R5 is selected from hydrogen, fluoro, and chloro, more preferablyhydrogen,

R8 is selected from fluoro, fluoromethyl, methoxy and fluoromethoxy,

R9 is hydrogen or fluoro,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano,cyanomethyl, cyanoethyl, cyanopropyl, cyanomethoxy, cyanoethoxy, nitro,azido, pentafluorosulfanyl, C₁₋₃alkyl, C₂₋₃alkenyl, C₂₋₃alkynyl,C₁₋₃alkyloxy, C₁₋₂alkylcarbonyl, cycylopropyl, cyclopropylmethyl, andcyclopropylmethoxy, wherein each group in R10 can be unsubstituted orsubstituted with one or more groups selected from fluoro, fluorinated orunsubstituted C₁₋₂alkyloxy, fluorinated or unsubstitutedC₁₋₂alkyloxycarbonyl and hydroxy,

R11 is selected from hydrogen, fluoro, chloro, fluoromethyl, methoxy andfluoromethoxy, and pharmaceutically acceptable salts, solvates, isotopesand co-crystals thereof.

In one preferred embodiment, in the compounds of Formula VI e,

m is 0 or 1,

n is 0 or 1, preferably 0,

Y is selected from fluoro, chloro, cyano, hydroxy, methyl and methoxy,wherein the methoxy and methyl group are optionally substituted with oneor more substituents selected from fluoro, chloro, bromo, hydroxy,methoxy and fluoromethoxy,

R2 and R4 are hydrogen,

R5 is hydrogen, fluoro, or chloro, preferably hydrogen,

R8 is selected from fluoro, fluoromethyl, methoxy and fluoromethoxy,preferably from fluoro and methoxy,

R9 is hydrogen or fluoro, preferably hydrogen,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano,cyanomethyl, cyanoethyl, pentafluorosulfanyl, C₁₋₃alkyl, C₂₋₃alkenyl,C₂₋₃alkynyl, C₁₋₃alkyloxy, C₁₋₂alkylcarbonyl and cyclopropyl, whereineach alkyl, alkenyl, alkynyl, alkyloxy and cyclopropyl group in R10 canbe unsubstituted or suitably substituted with one or more groupsselected from fluoro, fluorinated or unsubstituted C₁₋₂alkyloxy,fluorinated or unsubstituted C₁₋₂alkyloxycarbonyl and hydroxy, whereinsaid substituent is preferably selected from fluoro and fluorinated orunsubstituted C₁₋₂alkyloxy,

R11 is selected from hydrogen, fluoro, chloro, fluoromethyl, methoxy andfluoromethoxy, and pharmaceutically acceptable salts, solvates, isotopesand co-crystals thereof.

In one preferred embodiment, in the compounds of Formula VIM,

n is 0 or 1, preferably 0,

Y is selected from fluoro, chloro, cyano, hydroxy, methyl and methoxy,wherein the methoxy and methyl group are optionally substituted with oneor more substituents selected from fluoro, chloro, bromo, hydroxy,methoxy and fluoromethoxy,

R2 and R4 are both hydrogen,

R5 is hydrogen, fluoro, or chloro, preferably hydrogen,

R8 is selected from fluoro, fluoromethyl, methoxy and fluoromethoxy,

R9 is hydrogen or fluoro, preferably hydrogen,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano,cyanomethyl, cyanoethyl, pentafluorosulfanyl, C₁₋₃alkyl, C₂₋₃alkenyl,C₂₋₃alkynyl, C₁₋₃alkyloxy, C₁₋₂alkylcarbonyl and cyclopropyl, whereineach alkyl, alkenyl, alkynyl, alkyloxy and cyclopropyl group in R10 canbe unsubstituted or suitably substituted with one or more groupsselected from fluoro, fluorinated or unsubstituted C₁₋₂alkyloxy,fluorinated or unsubstituted C₁₋₂alkyloxycarbonyl and hydroxy, whereinsaid substituent is preferably selected from fluoro and fluorinated orunsubstituted C₁₋₂alkyloxy,

R11 is selected from hydrogen, fluoro, chloro, fluoromethyl, methoxy andfluoromethoxy, and pharmaceutically acceptable salts, solvates, isotopesand co-crystals thereof.

In one preferred embodiment, in the compounds of Formula VI g,

p is 0 or 1,

Y is selected from fluoro, chloro, cyano, hydroxy, methyl and methoxy,wherein the methoxy and methyl group are optionally substituted with oneor more substituents selected from fluoro, chloro, bromo, hydroxy,methoxy and fluoromethoxy,

R4 is hydrogen,

R5 is hydrogen or fluoro, preferably hydrogen,

R8 is selected from fluoro, fluoromethyl, methoxy and fluoromethoxy,

R9 is hydrogen or fluoro,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano,cyanomethyl, cyanoethyl, pentafluorosulfanyl, C₁₋₃alkyl, C₂₋₃alkenyl,C₂₋₃alkynyl, C₁₋₃alkyloxy, C₁₋₂alkylcarbonyl and cyclopropyl, whereineach alkyl, alkenyl, alkynyl, alkyloxy and cyclopropyl group in R10 canbe unsubstituted or suitably substituted with one or more groupsselected from fluoro, fluorinated or unsubstituted C₁₋₂alkyloxy,fluorinated or unsubstituted C₁₋₂alkyloxycarbonyl and hydroxy, whereinsaid substituent is preferably selected from fluoro and fluorinated orunsubstituted C₁₋₂alkyloxy,

R11 is selected from hydrogen, fluoro, chloro, fluoromethyl, methoxy andfluoromethoxy, and pharmaceutically acceptable salts, solvates, isotopesand co-crystals thereof.

In one preferred embodiment of the compounds of formula Vle-g, R10 isselected from chloro, cyano, cyanomethyl, cyanoethyl, C₁₋₃alkyl andC₁₋₃alkoxy, wherein each alkyl and alkoxy can be unsubstituted orsubstituted with one or more substituents selected from fluoro, methoxy,fluoromethoxy, ethoxy and fluoroethoxy, wherein in one embodiment R10 isselected from chloro, bromo, unsubstituted or fluorinated C₁₋₃alkoxy,cyano, cyanomethyl and cyanoethyl. In one preferred embodiment of thecompounds of formula Vle-g, R10 is chloro.

In one preferred embodiment of the compounds of formula Vle-g, Y, ifpresent, is selected from fluoro, chloro, cyano, hydroxy, methyl,fluoromethyl, hydroxymethyl, methoxy and fluoromethoxy. In one preferredembodiment of the compounds of formula VIg, Y is selected from fluoro,hydroxy, fluoromethyl, methoxy and fluoromethoxy.

In one preferred embodiment, in the compounds or Formula Vle to VIg, R10is selected from fluro, chloro, bromo, fluromethyl, fluoroethyl,fluoromethoxy, fluoroethoxy, cyano and cyanomethyl, and is particularlypreferably chloro.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I. I-2, II, II-2, IIa, II-2a, IIb, II-2, IIc, II-2c, Ild, II-2d,Ile, II-2e, Ilf, II-2f, IIg, II-2g, III, III-2, Illa, III-2a, IIIb,III-2b, IIIc, III-2c, IV, 2, V, V-2, VI, VIa, VIb, VIc, VId, VIe, VIf,or VIg, wherein R4 is hydrogen, and the other substitutions are asdisclosed herein.

Another embodiment relates to compounds of the present inventionincluding but not limited to those having a structure of Formula I, I-2,II, II-2, Ila, II-2a, Ilb, II-2b, IIc, II-2c, Ild, II-2d, Ile, II-2e,Ilf, II-2f, IIg, II-2g, III, III-2, Illa, III-2a, IIIb, III-2b, IIIc,III-2c, IV, I-2, V, V-2, VI, VIa, VIb, VIc, VId, VIe, VIf, or VIg,wherein R5 is selected from hydrogen, halogen, cyano, azido,unsubstituted or fluorinated C₁₋₂ alkyl, preferably methyl ortrifluoromethyl, unsubstituted or fluorinated C₁₋₂ alkyloxy,unsubstituted or fluorinated C₁₋₂ alkylcarbonyl, unsubstituted orfluorinated C₁₋₂ alkyloxycarbonyl, C₁₋₂ alkylsulfinyl preferablymethylsulfinyl, and C₁₋₂ alkylsulfonyl preferably methylsulfonyl, andthe other substitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, Ila, II-2a, Ilb, II-2b, IIc, II-2c, Ild,II-2d, Ile, II-2e, Ilf, II-2f, IIg, II-2g, III, III-2, Illa, III-2a,IIIb, III-2b, IIIc, III-2c, IV, IV-2, V, V-2, VI, VIa, VIb, VIc, VId,VIe, VIf, or VIg, wherein R5 is selected from hydrogen, fluoro, chloro,bromo, iodo, methyl, trifluoromethyl, methoxy and trifluoromethoxy, andis particularly preferably selected from hydrogen, fluoro, chloro andbromo, and the other substitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, IIa, II-2a, IIb, II-2b, IIc, II-2c, Ild,II-2d, Ile, II-2e, Ilf, II -2f, IIg, II-2g, Ill, III-2, Illa, III-2a,IIIb, III-2b, IIIc, III-2c, IV, IV-2, V, V-2, VI, VIa, VIb, VIc, VId,Vie, Vlf, or VIg, wherein R5 is iodo and R6 is hydrogen, and the othersubstitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, Ila, II-2a, Ilb, II-2b, IIc, II-2c, Ild,II-2d, Ile, II II-2e, Ilf, II-2f, IIg, II-2g, Ill, III-2, Illa, III-2a,IIIb, III-2b, IIIc, III-2c, IV, IV-2, V, V-2, VI, VIa, VIb, VIc, VId,Vle, Vlf, or VIg, wherein R5 is hydrogen, and the other substitutionsare as disclosed herein

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, Ild, II-2d, Ile, II-2e, Ilf, II-2f, IIg,II-2g, IV, IV-2, V, V-2, VI, VIa, VIb, or VIc, wherein R7, if present,is hydrogen, and the other substitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I I, 1-2, II, II-2, Ild, II-2d, Ile, II -2e, Ilf, II-2f, IIg,II-2g, IV, IV-2, V, V-2, VI, VIa, VIb, or VIc, wherein R7, if present,is fluoro, and the other substitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, Ild, II -2d, Ile, II -2e, Ilf, II-2f, IIg,II-2g, IV, IV-2, V, V-2, VI, VIa, VIb, or VIc, wherein R7, if present,is C₁₋₃ alkoxy or fluoro(C₁₋₃)alkoxy, preferably mono-, di- ortrifluoromethoxy, and the other substitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, IId, II-2d, Ile, II-2e, Ilf, II-2f, IIg,II-2g, IV, IV-2, V, V-2, VI, VIa, VIb, or VIc, wherein R7, if present,is methoxy, and the other substitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention, including but not limited to those having a structure ofFormula I, I-2, II, II-2, Ild, II-2d, Ile, II-2e, Ilf, II-2f, IIg,II-2g, IV, IV-2, V, V-2, VI, VIa, VIb, or VIc wherein R7, if present, isselected from hydrogen, cyano, fluoro, chloro, bromo, methoxy, ethoxy,fluoromethoxy, fluoroethoxy, methyl, ethyl, fluoromethyl, fluoroethyl,methylsulfinyl, fluoromethylsulfinyl, methylsulfonyl andfluoromethylsulfonyl, and the other substitutions are as disclosedherein.

Another preferred embodiment relates to compounds of the presentinvention, including but not limited to those having a structure ofFormula I, I-2, II, II-2, Ild, II-2d, Ile, II-2e, Ilf, II-2f, IIg,II-2g, IV, IV-2, V, V-2, VI, VIa, VIb, or VIc, wherein R7, if present,is methylsulfonyl, fluoromethylsulfonyl, methylsulfinyl, orfluoromethylsulfinyl, and the other substitutions are as disclosedherein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, Ild, II-2d, Ile, II-2e, Ilf, II-2f, IIg,II-2g, IV, IV-2, V, V-2, VI, VIa, VIb, or VIc, wherein R7 istrifluoromethyl, and the other substitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention, including but not limited to those having a structure ofFormula I, I-2, II, II-2, Ild, II-2d, Ile, II-2e, Ilf, II-2f, IIg,II-2g, IV, IV-2, V, V-2, VI, VIa, VIb, or VIc, wherein R7, if present,is cyano, cyanomethyl, or cyanomethoxy, and the other substitutions areas disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, Ild, II-2d, Ile, II-2e, Ilf, II-2f, IIg,II-2g, IV, IV-2, V, V-2, VI, VIa, VIb, or VIc, wherein R7 is bromo orchloro, preferably bromo, and the other substitutions are as disclosedherein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, IIc, II -2c, Ild, II-2d, Ile, II-2e, Ilf,II-2f, IIg, II-2g, Ill, III-2, IV, IV-2, V, V-2, VI, VIa, VIb, VIc, VId,Vle, Vlf, or VIg, wherein R8 is selected from hydrogen, fluoro, chloro,bromo, iodo, methoxy, methyl, and trifluoromethyl and the othersubstitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, IIc, II-2c, Ild, 11-2d, Ile, II-2e, Ilf,II-2f, IIg, II-2g, Ill, III-2, IV, IV-2, V, V-2, VI, VIa, VIb, VIc, VId,Vle, Vlf, or VIg, wherein R8 is selected from fluoro, chloro, cyano,methoxy and fluoromethoxy, and the other substitutions are as disclosedherein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, IIc, II-2c, Ild, II-2d, Ile, II-2e, Ill,III-2, IV, IV-2, V, V-2, VI, VIa, VIb, VIc, VId, Vle, Vlf, or VIg,wherein R9 is selected from hydrogen, fluoro, chloro, bromo, iodo,methoxy, methyl, cyano, and trifluoromethyl, and is preferably hydrogen,fluoro, chloro, or bromo and the other substitutions are as disclosedherein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, IIc, II-2c, Ild, II-2d, Ile, II-2e, III,III-2, IV, IV-2, V, V-2, VI, VIa, VIb, VIc, VId, Vle, Vlf, or VIg,wherein R9 is hydrogen, and the other substitutions are as disclosedherein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, Ila, II-2a, 1lb, II-2b, IIc, II-2c, Ild,II-2d, Ile, II-2e, Ilf, II-2f, IIg, 11-2g, Ill, III-2, Illa, III-2a,IIIb, III-2b, IIIc, III-2c, IV, IV-2, V, V-2, VI, VIa, VIb, VIc, VId,Vie, Vlf, or VIg, wherein R11 is selected from hydrogen, fluoro, chloro,bromo, iodo, methoxy, fluoromethoxy, methyl, cyano, and fluoromethylpreferably trifluoromethyl, and is more preferably selected fromhydrogen, methoxy, fluoromethoxy, fluoromethyl, fluoro, chloro andbromo, and the other substitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, Ila, II-2a, 1lb, II-2b, IIc, II-2c, Ild,II-2d, Ile, II-2e, Ilf, II-2f, IIg, II-2g, Ill, III-2, Illa, III-2a,IIIb, III-2b, IIIc, III-2c, IV, IV-2, V, or V-2, wherein X3 is C-R1 2and R12 is selected from hydrogen, fluoro, chloro, bromo, iodo, methoxy,methyl, and fluoro(C₁₋₃)alkyl preferably trifluoromethyl, and is morepreferably hydrogen, fluoro, chloro, or bromo, and the othersubstitutions are as disclosed herein. In a particularly preferredembodiment, R12 is hydrogen or fluoro.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, II-2, II, II-2, Ild, II-2d, Ile, II-2e, Ilf, II-2f, IIg,II-2g, Ill, III-2, Illa, III-2a, IIIb, III-2b, IIIc, III-2c, IV, IV-2,V, V-2, VI, VIa, VIb, VIc, and VId, wherein R6 is different fromhydrogen, and the other substitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, IId, II-2d, Ile, II-2e, Ilf, II-2f, IIg,II-2g, Ill, III-2, Illa, III-2a, IIIb, III-2b, IIIc, III-2c, IV, IV-2,V, V-2, VI, VIa, VIb, VIc, and VId, wherein R6 is selected from thegroup of halogen, cyclopropyl, cyclopropyloxy, cyclopropylmethyl,unsubstituted or fluorinated C₁₋₃ alkyl, unsubstituted or fluorinatedC₁₋₃ alkyloxy, unsubstituted or fluorinated phenyl, benzyloxy,thiophene, methylsulfinyl, methylsulfonyl, and cyclopropyl, and theother substitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those aving a structure ofFormula I, I-2, II, II-2, IId, II-2d, IIe, II-2e, IIf, II-2f, IIg,II-2g, Ill, III-2, IIIa, III-2a, IIIb, III-2b, IIIc, III-2c, IV, IV-2,V, V-2, VI, VIa, VIb, VIc, and VId, wherein R6 is selected from fluoro,chloro, bromo, methoxy, methyl, ethyl, isopropyl, cyclopropyl, phenyl,benzyloxy, 2-thiophene, 3-thiophene, trifluoromethyl, and the othersubstitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to having a structure of Formula I,I-2, II, II-2, IId, II-2d, Ile, II-2e, Ilf, II-2f, IIg, II-2g, Ill,III-2, Illa, III-2a, IIIb, III-2b, IIIc, III-2c, IV, IV-2, V, V-2, VI,VIa, VIb, VIc, and VId, wherein R6 is chloro or bromo, and the othersubstitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, IId, II-2d, Ile, 11-2e, Ilf, II-2f, IIg,II-2g, Ill, III-2, Illa, III-2a, IIIb, III-2b, IIIc, III-2c, IV, IV-2,V, V-2, VI, VIa, VIb, VIc and VId, wherein R6 is chloro, and the othersubstitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, IId, II-2d, Ile, II-2e, Ilf, II-2f, IIg,II-2g, IV, IV-2, V, V-2, VI, VIa, VIb, VIc and VId, wherein R6 isselected from halogen, cyano, C₁₋₃alkyl, C₁₋₃alkyloxy, C3-6 cycloalkyland C₃₋₆ cycloalkyloxy, each of which can be optionally substituted witha residue selected from fluoro and unsubstituted or fluorinatedC₁₋₃alkoxy.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, IId, II-2d, Ile, 11-2e, Ilf, II-2f, IIg,II-2g, IV, IV-2, V, V-2, VI, VIa, VIb, VIc, wherein R7 is selected fromhydrogen, halogen, cyano, C₁₋₃alkyl, C₁₋₃alkyloxy, C3-6 cycloalkyl andC₃₋₆ cycloalkyloxy, each of which can be optionally substituted with aresidue selected from fluoro and unsubstituted or fluorinatedC₁₋₃alkoxy.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, Ila, II-2a, 1lb, II-2b, IIc, II-2c, Ill,III-2, IV, IV-2, V and V-2, wherein X3 is C(R1 2), and the othersubstitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those structure of Formula I,I-2, II, II-2, Ila, II-2a, Ilb, II-2b, IIc, II-2c, Ill, III-2, IV, IV-2,V and V-2, wherein X3 is N and the other substitutions are as disclosedherein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, II, Ila, Ilb, IIc, Ill, or IV, wherein at least one of R8,R10 and R11 is different from hydrogen and unsubstituted alkyl.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, Ila, II-2a, Ilb, II-2b, IIc, III-2c, Ild,II-2d, Ile, II-2e, Ill, III-2, Illa, III-2a, IIIb, III-2b, IV, IV-2, V,V-2, VI, VIa, VIb, VIc, VId, Vle, Vlf, or VIg, wherein R10 is selectedfrom hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyl, halo(C₁₋₃)alkylpreferably fluoro(C₁₋₂)alkyl, C₂-₃ alkynyl, methoxy, ethoxy, propoxy,halo(C₁₋₃)alkyloxy preferably fluoro(C₁₋₂)alkyloxy, unsubstituted orfluorinated (C₁₋₂) alkoxy(C₁₋₃)alkoxy, cyano, cyanomethyl, azido,pentafluorosulfanyl, and nitro, and the other substitutions are asdisclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, 1-2, II, II-2, Ila, II-2a, Ilb, II-2b, IIc, II-2c, Ild,II-2d, Ile, II-2e, III, III-2, Illa, III-2a, IIIb, III-2b, IV, IV-2, V,V-2, VI, VIa, VIb, VIc, VId, Vie, Vlf, or VIg, wherein R10 is selectedfrom halogen, cyano, C₁₋₃alkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, C₁₋₃alkyloxy,C₃₋₆ cycloalkyl and C₃₋₆ cycloalkyloxy, each of which can be optionallysubstituted with a residue selected from fluoro, cyano and optionallyfluorinated C₁₋₃alkoxy.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, Ila, II-2a, Ilb, II-2b, IIc, II-2c, Ild,II-2d, Ile, II-2e, III, III-2, Illa, III-2a, IIIb, III-2b, IV, IV-2, V,V-2, VI, VIa, VIb, VIc, VId, Vle, Vlf, or VIg, wherein R10 is selectedfrom the group of cyano, cyanomethyl, halogen, azido, ethynyl,pentafluorosulfanyl, acetyl, difluoroethoxy, trifluoroethoxy,trifluoromethoxy and trifluoromethyl, and the other substitutions are asdisclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II -2, Ila, II-2a, Ilb, II-2b, IIc, II-2c, Ild,II-2d, Ile, II -2e, III, III-2, Illa, III-2a, IIIb, III-2b, IV, IV-2, V,V-2, VI, VIa, VIb, VIc, VId, Vle, Vlf, or VIg, wherein R10 is cyano,cyanomethyl, cyanoethyl, or cyanomethoxy and the other substitutions areas disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II -2, Ila, II-2a, Ilb, II-2b, IIc, II-2c, Ild, II-2d, Ile, II-2e, III, III-2, Illa, III-2a, IIIb, III-2b, IV, IV-2, V,V-2, VI, VIa, VIb, VIc, VId, Vle, Vlf, or VIg, wherein R10 is fluoro,and the other substitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II -2, Ila, II-2a, Ilb, II-2b, IIc, II-2c, Ild,II-2d, Ile, II-2e, III, III-2, Illa, III-2a, IIIb, III-2b, IV, IV-2, V,V-2, VI, VIa, VIb, VIc, VId, Vle, Vlf, or Vlg wherein R10 is chloro andthe other substitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II -2, IIa, II -2a, Ilb, II-2b, IIc, II-2c, Ild,II-2d, Ile, II-2e, III, III-2, Illa, III-2a, IIIb, III-2b, IV, IV-2, V,V-2, VI, VIa, VIb, VIc, VId, Vle, Vlf, or VIg, wherein R10 is bromo andthe other substitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II -2, IIa, II -2a, Ilb, II-2b, IIc, II-2c, Ild,II-2d, Ile, II-2e, Ill, III-2, Illa, III-2a, IIIb, III-2b, IV, IV-2, V,V-2, VI, VIa, VIb, VIc, VId, Vie, Vlf, or VIg, wherein R10 is mono-, di-or trifluoromethyl and the other substitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II -2, IIa, II -2a, Ilb, II-2b, IIc, II-2c, Ild,11-2d, Ile, 11-2e, Ill, III-2, Illa, III-2a, IIIb, III-2b, IV, IV-2, V,V-2, VI, VIa, VIb, VIc, VId, Vle, Vlf, or VIg, wherein R10 isdifluoroethoxy (—OCH₃CHF₂) and the other substitutions are as disclosedherein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II -2, IIa, II -2a, Ilb, II-2b, IIc, II-2c, Ild,II-2d, Ile, II-2e, Ill, III-2, Illa, III-2a, IIIb, III-2b, IV, IV-2, V,V-2, VI, VIa, VIb, VIc, VId, Vle, Vlf, or VIg, wherein R10 istrifluoroethoxy (—OCH₃CF₃) and the other substitutions are as disclosedherein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II -2, IIa, II -2a, Ilb, II-2b, IIc, II-2c, Ild,II-2d, Ile, II -2e, Ill, III-2, Illa, III-2a, IIIb, III-2b, IV, IV-2, V,V-2, VI, VIa, VIb, VIc, VId, Vle, Vlf, or VIg, wherein R10 is ethynyland the other substitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention, wherein R10 is selected from methoxymethyl, methoxyethyl,methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl,methoxyethenyl, methoxypropenyl, ethoxyethenyl, ethoxypropenyl,methoxyethynyl, methoxypropynyl, methoxymethoxy, methoxyethoxy,methoxypropoxy, ethoxymethoxy, ethoxyethoxy, ethoxypropoxy andpropoxymethoxy, each of which may be unsubstituted or fluorinated up tothree times, and the other substitutions are as disclosed herein.

Another preferred embodiment relates to compounds of the presentinvention, wherein R10 is methoxypropyl or fluorinated methoxypropyl,and the other substitutions are as disclosed herein.

Another particularly preferred embodiment relates to compounds of thepresent invention, as further described herein, wherein R8, R10 and R11are all different from hydrogen, and the other substitutions are asdisclosed herein.

Another particularly preferred embodiment relates to compounds of thepresent invention including but not limited to those having a structureof Formula I, II, Ill, or IV, as further described herein, wherein R6,R8, and R10 are all different from hydrogen and the other substitutionsare as disclosed herein.

Another particularly preferred embodiment relates to compounds of thepresent invention including but not limited to those having a structureof Formula I, II, Ill, or IV, as further described herein, wherein R6,R8, R10 and R11 are all different from hydrogen, and the othersubstitutions are as disclosed herein.

Another embodiment relates to compounds of the present invention, asfurther described herein, wherein at least one of R5, R6 and R7 isdifferent from hydrogen and the other substitutions are as disclosedherein.

Another embodiment relates to compounds of the present invention asfurther described herein, wherein at least one of R6 and R7 is differentfrom hydrogen and the other substitutions are as disclosed herein.

Another embodiment relates to compounds having a structure of FormulaIII, as further described herein, wherein at least one of R6 and R5 isdifferent from hydrogen and the other substitutions are as disclosedherein.

In one preferred embodiment, in the compounds of the present invention,R10 and at least one of R5, R6 and R7 are different from hydrogen andare independently selected from a group as further defined herein.

In one preferred embodiment, in the compounds of the present invention,R6 and R10 are different from hydrogen and are independently selectedfrom a group as further defined herein.

In one preferred embodiment, in the compounds of the present invention,R6, R10 and at least one of R8 and R11 are different from hydrogen andare independently selected from a group as further defined herein.

In one preferred embodiment, in the compounds of the present invention,R6, R8 and R11 are all different from hydrogen, and are independentlyselected from a group as further defined herein.

In one preferred embodiment, in the compounds of the present invention

-   -   (a) at least one of R5, R6 and R7, if R7 is present, and    -   (b) at least one of R8, R10 and R11

is different from hydrogen.

In one preferred embodiment, in the compounds of the present invention,R6, R7, if present, R8, R10 and R11 are all different from hydrogen andare independently selected from a group as further defined herein.

In one preferred embodiment, in the compounds of the present invention,R4 is hydrogen, and R6, R8, R10 and R11 are all different from hydrogenand are independently selected from a group as further defined herein.

In one preferred embodiment, in the compounds of the present invention,R4, R5 and R9 are all hydrogen, and R6, R8, and R10 are all differentfrom hydrogen and are independently selected from a group as furtherdefined herein

In one preferred embodiment, in the compounds of the present invention,R4, R5, R9 and R12, if present, are all hydrogen, and R6, R8, and R10are all different from hydrogen and are independently selected from agroup as further defined herein.

In one preferred embodiment, in the compounds of the present invention,R4 and R12, if present, are both hydrogen, R5 and R9 are independentlyhydrogen or fluoro, and R6, R8, R10 and R11 are all different fromhydrogen and are independently selected from a group as further definedherein.

In one preferred embodiment, in the compounds of the present invention,R4, R5, R9 and R12, if present, are all hydrogen, and R6, R8, R10 andR11 are all different from hydrogen and are independently selected froma group as further defined herein

In one preferred embodiment, in the compounds of the present invention,R4 and R12, if present, are both hydrogen, R5 and R9 are independentlyhydrogen or fluoro, and R6, R7, R8, R10 and R11 are all different fromhydrogen and are independently selected from a group as further definedherein

In one preferred embodiment, in the compounds of the present invention,R2, R4, R5, R9 and R12, if present, are all hydrogen, and R6, R7, R8,R10 and R11 are all different from hydrogen and are independentlyselected from a group as further defined herein.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, II, Ill, or IV, wherein R4 and R5 are both hydrogen, R6 ischloro or bromo, X3 is CR12, R8 and R11 are both selected from halogenpreferably fluoro and methoxy, R10 is selected from the group of fluoro,chloro, bromo, iodo, cyano, cyanomethyl, azido, acetyl, ethynyl,difluoroethoxy, trifluoroethoxy, and trifluoromethyl, and R9 and R12 areboth hydrogen.

Another particularly preferred embodiment relates to compounds of thepresent invention including but not limited to those having a structureof Formula I, II, Ila, Ilb, IIc, Ill, or IV, as further describedherein, wherein R8 and R9 together with the ring to which they areattached form a 2,1,3 benzothiadiazole and the other substitutions areas disclosed herein. In one aspect of this embodiment, R10, R11 and R12are all hydrogen.

Another particularly preferred embodiment relates to compounds of thepresent invention including but not limited to those having a structureof Formula I, II, Ila, Ilb, IIc, Ill, or IV, as further describedherein, wherein R10 and R9 together with the ring to which they areattached form a 2,1,3 benzothiadiazole and the other substitutions areas disclosed herein. In one aspect of this embodiment, R10 and R11 areboth hydrogen and R12 is hydrogen, fluoro or chloro.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, IIa, II-2a, Ilb, II-2b, IIc, II-2c, Ild,II-2d, Ile, II-2e, Ilf, II-2f, IIg, II-2g, III, III-2, IIla, III-2a,IIIb, III-2b, IIIc, III-2c, IV, IV-2, V, V-2, VI, VIa, VIb, VIc, VId,VIe, VIf, or VIg, and comprising at least one ¹⁸F isotope, preferably inthe position of a fluoro atom as indicated in one of the compoundsdisclosed herein. By way of non-limiting example, in the compound6-chloro-N-[2-fluoro-4-(pentafluorosulfanyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide, disclosed herein, atleast one of the six fluoros may by represented by or may comprise asuitable amount of the ¹⁸F isotope. As another example, the fluoro inthe compound7-bromo-6-chloro-N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamidemay be represented by or include an amount of ¹⁸F that is measurable bya suitable PET equipment. This applies likewise to other fluorocontaining compounds described herein. These ¹⁸F containing compoundscan preferably be used as PET tracers.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, I-2, II, II-2, IIa, II -2a, Ilb, II-2b, IIc, II-2c, Ild,11-2d, Ile, 11-2e, Ilf, II-2f, IIg, II-2g, III, III-2, Illa, III-2a,IIIb, III-2b, IIIc, III-2c, IV, IV-2, V, V-2, VI, VIa, VIb, VIc, VId,VIe, VIf, or Vlg and comprising at least one ¹¹C isotope preferably inthe position of a carbon atom as indicated herein. These ¹¹C containingcompounds can preferably be used as PET tracers.

Another preferred embodiment relates to compounds of the presentinvention including but not limited to those having a structure ofFormula I, 1-2, II, II-2, IIa, II -2a, Ilb, II-2b, IIc, II-2c, Ild,11-2d, Ile, 11-2e, Ilf, II-2f, IIg, II-2g, Ill, III-2, Illa, III-2a,IIIb, III-2b, IIIc, III-2c, IV, IV-2, V, V-2, VI, VIa, VIb, VIc, VId,VIe, VIf, or VIg, and comprising at least one ¹²³I, ¹²⁵Ior ¹³¹I isotope,preferably in the position of a iodine atom as indicated herein. By wayof non-limiting example, in the compoundN-(4-cyanophenyI)-5-iodo-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,disclosed herein, the iodine may be represented by a ¹²³1, ¹²⁵1 or ¹³¹1isotope.

This applies likewise to other iodine containing compounds describedherein. These ¹²³I, ¹²⁵l or ¹³¹I containing compounds can preferably beused as SPECT tracers.

One embodiment relates to any one of the compounds of the inventionwhich is specifically disclosed herein.

A preferred embodiment relates to a compound selected from the list of:

6-chloro-N-(4-ethynylphenyI)-1H-indole-3-sulfonamide

6-chloro-N-(5-cyanopyridin-2-yl)-1H-indole-3-sulfonamide

7-chloro-N-(4-chloro-2,5-difluorophenyI)-6-(methylsulfinyl)-1H-indole-3-sulfonamide

6-chloro-N-[3-fluoro-5-(methoxymethyl)pyridin-2-yl]-1H-indole-3-sulfonamide

6-chloro-N-(5-iodo-3-methylpyridin-2-yl)-1H-indole-3-sulfonamide

N-(4-chloro-2-fluorophenyl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide

N-(2,5-difluorophenyl)-6-methyl-1H-indole-3-sulfonamide

N-(4-chloro-2-fluorophenyl)-6-(tetrahydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-(pyridin-3-yl)-1H-indole-3-sulfonamide

N-(2,2,6-trifluoro-1,3-benzodioxo1-5-yl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

6-cyano-N-(2,2,6-trifluoro-1,3-benzodioxo1-5-yl)-1H-indole-3-sulfonamide

6-chloro-N-(7-cyano-2,1,3-benzothiadiazol-4-yl)-1H-indole-3-sulfonamide

N-(2,1,3-benzothiadiazol-4-yl)-7-bromo-1H-indole-3-sulfonamide

N-(2,1,3-benzothiadiazol-4-yl)-6-methoxy-1H-indole-3-sulfonamide

6-chloro-N-[2,5-difluoro-4-(pyridin-2-ylmethoxy)phenyI]-1H-indole-3-sulfonamide

6-chloro-N-(3-fluoro-5-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(4-chloro-2-fluorophenyl)-6-(3-hydroxyprop-1-en-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide6-chloro-N-(7-fluoro-2,1,3-benzoxadiazol-4-yl)-1H-indole-3-sulfonamide

N-(2,5-difluorophenyI)-6-(methylsulfonyl)-1H-indole-3-sulfonamide

N-(4-cyano-2,5-difluorophenyI)-6-(2-methoxyethoxy)-1H-indole-3-sulfonamide

N-(4-chloro-2,5-difluorophenyI)-6,7,8,9-tetrahydro-1H-benzo[g]indole-3-sulfonamide

6-chloro-N-{2-fluoro-4-[(1E)-3-methoxyprop-1-en-1-yl]phenyl}-1H-indole-3-sulfonamide

N-(2,2-difluoro-1,3-benzodioxo1-4-yl)-5-iodo-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(4,6-dichloropyridin-2-yI)-1H-indole-3-sulfonamide

6-chloro-N-(2,3-difluorophenyI)-1H-indole-3-sulfonamide

N-(2-fluoro-4-iodophenyl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide

N-(1,3-benzodioxo1-4-yl)-6-methyl-1H-indole-3-sulfonamide

6-chloro-N-(2-chlorophenyI)-1H-indole-3-sulfonamide

5-bromo-N-(4-cyanophenyI)-1H-indole-3-sulfonamide

N-(4-bromo-2,5-difluorophenyI)-6-chloro-1H-indole-3-sulfonamide

6-bromo-N-(4-cyano-2,5-difluorophenyI)-1H-indole-3-sulfonamide

6-chloro-N[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamide

N-(4-chloro-2,5-difluorophenyI)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

N-(4-bromo-2,5-difluorophenyI)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

6-chloro-N-(4-chloro-2,5-difluorophenyI)-1H-indole-3-sulfonamide

6-chloro-N[4-(difluoromethoxy)-2,5-difluorophenyl]-1H-indole-3-sulfonamide

N[4-(cyanomethyl)-2,5-difluorophenyl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

6-bromo-N-[3,6-difluoro-5-(3-methoxypropyl)pyridin-2-yI]-1H-indole-3-sulfonamide

N-(5-bromo-3,6-difluoropyridin-2-yI)-6-chloro-1H-indole-3-sulfonamide

N-(4-bromo-2,5-difluorophenyI)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-7-fluoro-1H-indole-3-sulfonamide

N-(4-cyano-2-fluorophenyl)-1H-benzo[g]indole-3-sulfonamide

6-chloro-N-[3,6-difluoro-5-(3-methoxypropyl)pyridin-2-yI]-1H-indole-3-sulfonamide

5-bromo-6-chloro-N[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamide

6-chloro-N-(5-chloro-3,6-difluoropyridin-2-yI)-1H-indole-3-sulfonamide

6-chloro-N-(4-chloro-2,5-difluorophenyI)-7-fluoro-1H-indole-3-sulfonamide

N-(4-cyano-2,5-difluorophenyI)-1H-benzo[g]indole-3-sulfonamide

N-(5-chloro-3-fluoro-6-methoxypyridin-2-yI)-1H-benzo[g]indole-3-sulfonamide

7-bromo-6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-1H-indole-3-sulfonamide

6-chloro-N-[4-(cyanomethoxy)-2,5-difluorophenyl]-1H-indole-3-sulfonamide

N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

6-chloro-N-(4-cyano-5-fluoro-2-methoxyphenyl)-1H-indole-3-sulfonamide

6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-1H-indole-3-sulfonamide

6-chloro-N-(5-ethyl-3,6-difluoropyridin-2-yl)-1H-indole-3-sulfonamide

6-chloro-N-{5-[(E)-2-ethoxyethenyl]-3,6-difluoropyridin-2-y}-1-1H-indole-3-sulfonamide

6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-methoxy-1H-indole-3-sulfonamide

6-chloro-N-(4-chloro-2-fluorophenyl)-1H-indole-3-sulfonamide

ethyl3-(6-{[(6-chloro-1H-indo1-3-yl)sulfonyl]amino}-2,5-difluoropyridin-3-yl)propanoate

6-chloro-N-[2,5-difluoro-4-(trifluoromethyl)phenyl]-1H-indole-3-sulfonamide

6-bromo-N-{3,6-difluoro-5-[(1E)-3-methoxyprop-1-en-1-yl]pyridin-2-yl}-1-1H-indole-3-sulfonamide

6-chloro-N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1-benzothiophene-3-sulfonamide

N-(2,1,3-benzothiadiazol-4-yl)-6-bromo-1H-indole-3-sulfonamide

6-chloro-N-[4-(2,2-difluoroethoxy)-2,5-difluorophenyl]-1H-indole-3-sulfonamideethyl(2E)-3-(6-{[(6-chloro-1H-indo1-3-yl)sulfonyl]amino}-2,5-difluoropyridin-3-yl)prop-2-enoate

N-(5-chloro-3-fluoropyridin-2-yl)-1H-benzo[g]indole-3-sulfonamide

N-(4-chloro-2,5-difluorophenyl)-8-(difluoromethyl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

6-chloro-N-(4-chloro-2,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-7-methoxy-1H-indole-3-sulfonamide

6-chloro-N[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-7-fluoro-1H-indole-3-sulfonamide

6-chloro-N-(2,5-difluoro-4-iodophenyl)-1H-indole-3-sulfonamide

N-(4-cyano-5-fluoro-2-methoxyphenyl)-1H-benzo[g]indole-3-sulfonamide

N[4-(cyanomethoxy)-2,5-difluorophenyl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

N-(4-cyano-2,5-difluorophenyl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide

6-chloro-N-(6-fluoro-2,1,3-benzothiadiazol-5-yl)-1H-indole-3-sulfonamide

6-chloro-N[4-(difluoromethoxy)-2,5-difluorophenyl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(2,1,3-benzoselenadiazol-4-yl)-6-chloro-1H-indole-3-sulfonamide

6-chloro-N-[2,5-difluoro-4-(trifluoromethyl)phenyI]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-{3,6-difluoro-5-[(1E)-3-methoxyprop-1-en-1-yl]pyridin-2-yl}-1-1H-indole-3-sulfonamide

6-chloro-N-(4-cyano-2-fluorophenyI)-1H-indole-3-sulfonamide

6-chloro-N-(2,5-difluoro-4-methylphenyI)-1H-indole-3-sulfonamide

6-chloro-N[5-(2-ethoxyethyl)-3,6-difluoropyridin-2-yl]-1H-indole-3-sulfonamide

6-chloro-N-(5-chloro-3,6-difluoropyridin-2-yI)-7-methoxy-1H-indole-3-sulfonamide

N-(4-cyano-2-fluorophenyl)-6-(thiophen-2-yl)-1H-indole-3-sulfonamide

6-chloro-N-(4-ethynyl-2-fluorophenyl)-1H-indole-3-sulfonamide

6-chloro-N[3-fluoro-5-(trifluoromethyppyridin-2-yl]-1H-indole-3-sulfonamide

6-chloro-N[2-fluoro-4-(trifluoromethyl)phenyl]-1H-indole-3-sulfonamide

7-bromo-6-chloro-N-(4-cyano-2-fluorophenyI)-1H-indole-3-sulfonamide

6-bromo-N-(4-cyano-2-fluorophenyI)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(4-cyano-2,5-difluorophenyI)-1H-indole-3-sulfonamide

6-bromo-N-(2-fluoro-4-iodophenyI)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(5-bromo-6-fluoro-3-methoxypyridin-2-yI)-6-chloro-1H-indole-3-sulfonamide

6-chloro-N-(2-fluoro-4-iodophenyI)-1H-indole-3-sulfonamide

6-chloro-N[5-(cyanomethyl)-6-fluoro-3-methoxypyridin-2-yl]-1H-indole-3-sulfonamide

6-bromo-7-chloro-N-(4-chloro-2,5-difluorophenyI)-1H-indole-3-sulfonamide

6-bromo-N-(6-fluoro-2,1,3-benzothiadiazol-5-yl)-1H-indole-3-sulfonamide

N-(4-bromo-2,5-difluorophenyI)-6-methoxy-1H-indole-3-sulfonamide

6-bromo-N-(4-cyano-2-fluorophenyI)-1H-indole-3-sulfonamide

6-chloro-N-(4-cyano-2-fluoro-5-methoxyphenyI)-1H-indole-3-sulfonamide

N-(5-chloro-3,6-difluoropyridin-2-yI)-1H-benzo[g]indole-3-sulfonamide

6-azido-N[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamide

6-chloro-N-[3,6-difluoro-5-(2-fluoroethoxy)pyridin-2-yl]-1H-indole-3-sulfonamide

6-chloro-N-(6-fluoro-1-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-1H-indole-3-sulfonamide

N-(4-chloro-2,5-difluorophenyl)-5H[1,3]dioxolo[4,5-f]indole-7-sulfonamide

6-bromo-N-(5-chloro-3-fluoropyridin-2-yl)-1H-indole-3-sulfonamide

N-[4-(cyanomethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-1H-indole-3-sulfonamide

N-(2,1,3-benzothiadiazol-4-yl)-1H-benzo[g]indole-3-sulfonamide

6-bromo-N-(4-chloro-2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-(2,2-difluoroethoxy)-1H-indole-3-sulfonamide

6-bromo-N-(4-cyanophenyl)-1H-indole-3-sulfonamide

N-(2,1,3-benzothiadiazol-5-yl)-6-bromo-1H-indole-3-sulfonamide

N-(4-cyano-2-fluorophenyl)-6-(propan-2-yl)-1H-indole-3-sulfonamide

N-(4-cyano-2-fluorophenyl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide

N-(4-cyano-2,5-difluorophenyl)-6-methoxy-1 H-indole-3-sulfonamide

N-(4-bromo-2,5-difluorophenyl)-6-methoxy-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(5-ethenyl-3,6-difluoropyridin-2-yl)-1 H-indole-3-sulfonamide

N-(4-bromo-2,5-difluorophenyl)-6-(methylsulfinyl)-1H-indole-3-sulfonamide

N-(4-bromo-2,5-difluorophenyl)-6-chloro-1-benzofuran-3-sulfonamide

N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(methylsulfinyl)-1H-indole-3-sulfonamide

6-chloro-N-(2,4,5-trifluorophenyl)-1 H-indole-3-sulfonamide

N-(4-chloro-2,5-difluorophenyl)-8-hydroxy-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

6-chloro-N-(2,5-difluoro-4-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-cyano-1H-indole-3-sulfonamide

6-chloro-N[5-(cyanomethyl)-3-methoxypyridin-2-yl]-1H-indole-3-sulfonamide

N-[4-(2-cyanoethyl)-2,5-difluorophenyl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

6-chloro-N-[4-(cyanomethyl)-2-fluorophenyl]-1 H-indole-3-sulfonamide

N-(4-cyano-2-fluorophenyl)-1,6,7,8-tetrahydrocyclopenta[g]indole-3-sulfonamide

N-(2,1,3-benzothiadiazol-4-yl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

N-(4-chloro-2,5-difluorophenyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(4-ethynyl-2-fluorophenyl)-1 H-pyrrolo[3,2-h]quinoline-3-sulfonamide

N-(4-bromo-2-fluorophenyl)-6-chloro-1 H-indole-3-sulfonamide

6-bromo-N-(5-chloro-3-fluoropyridin-2-yl)-7-methyl-1H-indole-3-sulfonamide

6-chloro-N-[4-chloro-5-(difluoromethoxy)-2-fluorophenyl]-1H-indole-3-sulfonamide

N-(2,1,3-benzoxadiazol-5-yl)-6-chloro-1H-indole-3-sulfonamide

5-bromo-6-chloro-N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide

6-(benzyloxy)-N-(4-cyano-2,5-difluorophenyl)-1 H-indole-3-sulfonamide

N-(6-fluoro-2,1,3-benzothiadiazol-5-yl)-1H-benzo[g]indole-3-sulfonamide

N-(2,1,3-benzothiadiazol-4-yl)-6-chloro-1H-indole-3-sulfonamide

6-chloro-N-(3,6-difluoro-5-methylpyridin-2-yl)-1H-indole-3-sulfonamide

6-chloro-N-(4-cyanophenyl)-1 H-indole-3-sulfonamide

6-chloro-N-(5-chloro-3-fluoropyridin-2-yl)-1H-indole-3-sulfonamide

N-(4-chloro-2,5-difluorophenyl)-6-methoxy-1H-indole-3-sulfonamide

N-(4-chloro-2,5-difluorophenyl)-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(3-chloro-4-cyanophenyl)-1 H-indole-3-sulfonamide

7-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-6-fluoro-1H-indole-3-sulfonamide

6-chloro-N-[2-fluoro-4-(pentafluoro-lambda-6--sulfanyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(4-cyanophenyl)-1H-benzo[g]indole-3-sulfonamide

N-(4-chloro-2-fluorophenyl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-5,7-difluoro-1H-indole-3-sulfonamide

N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-6-nitro-1H-indole-3-sulfonamide

6-chloro-N-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-[4-(cyanomethoxy)-2,5-difluorophenyl]-1-benzofuran-3-sulfonamide

N-(4-chloro-2,5-difluorophenyl)-6-cyano-1H-indole-3-sulfonamide

6-chloro-N-(2,2-difluoro-1,3-benzodioxo1-4-yl)-1H-indole-3-sulfonamide

6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-(methylsulfinyl)-1H-indole-3-sulfonamide

6-chloro-N-[3,6-difluoro-5-(propan-2-yl)pyridin-2-yl]-1H-indole-3-sulfonamide

6-chloro-N-(4-chloro-2,5-difluorophenyl)-1-benzofuran-3-sulfonamide

7-chloro-N-(4-chloro-2,5-difluorophenyl)-6-(methylsulfanyl)-1H-indole-3-sulfonamide

N-(2,1,3-benzothiadiazol-4-yl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-{5-[(difluoromethoxy)methyl]-3-fluoropyridin-2-yl}-1-1H-indole-3-sulfonamide

N-(1,3-benzodioxo1-4-yl)-6-chloro-1H-indole-3-sulfonamide

6-(benzyloxy)-N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide

6-chloro-N-(3,6-difluoro-5-methylpyridin-2-yl)-7-fluoro-1H-indole-3-sulfonamide

N-(4-cyanophenyl)-6-cyclopropyl-1H-indole-3-sulfonamide

6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-5-fluoro-1H-indole-3-sulfonamide

7-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-6-methoxy-1H-indole-3-sulfonamide

6-chloro-N-(4-cyano-5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(6-fluoro-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-1H-indole-3-sulfonamide

ethyl 2-(6-{[(6-chloro-1H-indo1-3-yl)sulfonyl]ami no}-2,5-difl uoropyridin-3-yl)cyclopropanecarboxylate

N-(2,1,3-benzoxadiazol-4-yl)-6-chloro-1H-indole-3-sulfonamide

6-chloro-N-(4-cyanophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(4-chloro-2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(2,1,3-benzoxadiazol-4-yl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

6-chloro-N-(4-chloro-5-fluoro-2-methoxyphenyl)-1 H-indole-3-sulfonamide

6-chloro-N-(4-chloro-2,5-difluorophenyl)-1-benzothiophene-3-sulfonamide

6-chloro-N-[4-(cyanomethoxy)-2,5-difluorophenyl]-1-benzothiophene-3-sulfonamide

N-(2,1,3-benzothiadiazol-4-yl)-6-bromo-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-bromo-N-(4-cyanophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(4-cyano-2,6-difluorophenyl)-1H-indole-3-sulfonamide

6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(5-bromo-3-fluoropyridin-2-yl)-6-chloro-1H-indole-3-sulfonamide

6-chloro-N-(4-cyano-2-fluorophenyl)-5-fluoro-1H-indole-3-sulfonamide

N-(2,2-difluoro-1,3-benzodioxo1-4-yl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

N-(5-chloro-3,6-difluoropyridin-2-yI)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

N-(4-bromo-2-fluorophenyl)-6-methyl-1H-indole-3-sulfonamide

6-bromo-N-(4-chloro-2,5-difluorophenyI)-4-fluoro-1H-indole-3-sulfonamide

N-(2,1,3-benzothiadiazol-5-yl)-6-chloro-1H-indole-3-sulfonamide

N-(4-cyano-2-fluorophenyl)-6-methoxy-1 H-indole-3-sulfonamide

N-(4-chloro-2,5-difluorophenyI)-6-methoxy-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-cyano-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-1H-indole-3-sulfonamide

N-(4-chloro-2,5-difluorophenyl)-6-(methylsulfinyl)-1H-indole-3-sulfonamide

6-chloro-N-(6-fluoro-2,1,3-benzoxadiazol-5-yl)-1H-indole-3-sulfonamide

6-chloro-N-(3,5-difluoro-6-methoxypyridin-2-yl)-1 H-indole-3-sulfonamide

N-(4-cyano-5-fluoro-2-methoxyphenyI)-6-methoxy-1H-indole-3-sulfonamide

N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(4-cyano-2-fluorophenyl)-6-(thiophen-3-yl)-1H-indole-3-sulfonamide

N-(4-azido-2-fluorophenyl)-6-chloro-1 H-indole-3-sulfonamide

6-chloro-N-[2-fluoro-4-(trifluoromethoxy)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(2-fluoro-4-iodophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(5-bromo-6-chloropyridin-2-yl)-6-chloro-1H-indole-3-sulfonamide

N-(5-bromo-3-methoxypyridin-2-yl)-6-chloro-1H-indole-3-sulfonamide

6-chloro-N-[3-methoxy-5-(trifluoromethyppyridin-2-yl]-1H-indole-3-sulfonamide

6-chloro-N-(2,5-difluorophenyI)-1H-indole-3-sulfonamide

6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-1-benzothiophene-3-sulfonamide

6-chloro-N-(4-chloro-2,5-difluorophenyI)-7-(methylsulfonyl)-1H-indole-3-sulfonamide

6-chloro-N-(4-chloro-2,5-difluorophenyI)-5-fluoro-1H-indole-3-sulfonamide

N-(2-fluoro-4-iodophenyI)-5H-[1,3]dioxolo[4,5-f]indole-7-sulfonamide

N-[4-(cyanomethoxy)-2,5-difluorophenyl]-6-fluoro-1H-indole-3-sulfonamide

N-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methoxy-1H-indole-3-sulfonamide

6-chloro-N-[2-fluoro-4-(pentafluoro-lambda-6--sulfanyl)phenyl]-1H-indole-3-sulfonamide

6-bromo-N-(2,4,5-trifluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(2-fluoro-4-iodophenyl)-6-(methylsulfonyl)-1 H-indole-3-sulfonamide

6-chloro-N-(7-fluoro-2,1,3-benzothiadiazol-4-yl)-1H-indole-3-sulfonamide

6-chloro-N-(3,6-difluoro-5-methylpyridin-2-yl)-7-(trifluoromethyl)-1H-indole-3-sulfonamide

6-chloro-N-(3,5-difluoro-6-methoxypyridin-2-yI)-7-fluoro-1H-indole-3-sulfonamide

6-chloro-N-[2-fluoro-4-(trifluoromethoxy)phenyl]-1H-indole-3-sulfonamide

6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yI)-1-benzofuran-3-sulfonamide

6-chloro-N-(5-chloro-3-fluoro-6-methylpyridin-2-yI)-1H-indole-3-sulfonamide

N-(5-chloro-3-fluoro-6-methoxypyridin-2-yI)-6,7,8,9-tetrahydro-1H-benzo[g]indole-3-sulfonamide

6-bromo-N-(4-ethynylphenyI)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(2,2,6-trifluoro-1,3-benzodioxo1-5-yl)-1H-indole-3-sulfonamide

6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-indole-3-sulfonamide

6-chloro-N-[5-chloro-3-fluoro-6-(fluoromethyppyridin-2-yl]-1H-indole-3-sulfonamide

6-chloro-N-(3-fluoro-5-methylpyridin-2-yI)-1H-indole-3-sulfonamide

6-chloro-N-(2,5-difluoro-4-methoxyphenyI)-1H-indole-3-sulfonamide

N-(4-chloro-2-fluorophenyl)-6-methyl-1H-indole-3-sulfonamide

N-(5-chloro-3,6-difluoropyridin-2-yI)-1,6,7,8-tetrahydrocyclopenta[g]indole-3-sulfonamide

5-bromo-6-chloro-N-(4-chloro-2,5-difluorophenyl)-1H-indole-3-sulfonamide

6-chloro-N-(5-chloro-3,6-difluoropyridin-2-yl)-7-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-indole-3-sulfonamide

6-bromo-N-(2-chloro-3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(5-chloro-3,6-difluoropyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-azido-N-(4-cyano-2-fluorophenyI)-1H-indole-3-sulfonamide

6-(methylsulfonyl)-N-(2,2,6-trifluoro-1,3-benzodioxo1-5-yl)-1H-indole-3-sulfonamide

6-chloro-N-[3,6-difluoro-5-(prop-1-en-2-yl)pyridin-2-yI]-1H-indole-3-sulfonamide

N-(5-chloro-3-fluoropyridin-2-yl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

N-(2,1,3-benzothiadiazol-4-yl)-6-fluoro-1H-indole-3-sulfonamide

6-chloro-N-(5-chloro-2-fluorophenyl)-1H-indole-3-sulfonamide

N-(4-chloro-5-fluoro-2-methoxyphenyl)-1 H-benzo[g]indole-3-sulfonamide

6-chloro-7-(difluoromethoxy)-N-(3,5-difluoro-6-methoxypyridin-2-yl)-1H-indole-3-sulfonamide

N-(4-chloro-2-fluorophenyl)-6-(methylsulfonyl)-1 H-indole-3-sulfonamide

6-bromo-N-(2,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(1,3-benzodioxo1-4-yl)-6-bromo-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(2,1,3-benzothiadiazol-4-yl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide

6-chloro-N-(2-chloro-3,5-difluorophenyl)-1 H-indole-3-sulfonamide

6-amino-N[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamide

6-amino-N[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamide

6-(benzylsulfinyl)-N-(4-chloro-2,5-difluorophenyl)-1H-indole-3-sulfonamide

6-chloro-N-(3,6-difluoropyridin-2-yl)-1H-indole-3-sulfonamide

6-chloro-N-(2-fluoro-4-methylphenyl)-1H-indole-3-sulfonamide

N-(4-bromo-2-fluorophenyl)-6-methoxy-1H-indole-3-sulfonamide

N-(4-cyano-2-fluorophenyl)-6-(2,2,2-trifluoroethoxy)-1H-indole-3-sulfonamide

N-(4-cyanophenyl)-6-(methylsulfonyl)-1H-indole-3-sulfonamide

N-(2,4,5-trifluorophenyl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

6-chloro-N-(5-iodopyridin-2-yl)-1H-indole-3-sulfonamide

N-(4-cyano-2-fluorophenyl)-6-(cyclopropylmethoxy)-1H-indole-3-sulfonamide

N-(4-ethynyl-2-fluorophenyl)-6-methoxy-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-fluoro-N-(2-fluoro-4-iodophenyl)-1H-indole-3-sulfonamide

6-chloro-N-(5-chloropyridin-2-yl)-1 H-indole-3-sulfonamide

6-chloro-N-(4-cyano-2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(4-cyano-2-methoxyphenyl)-1H-indole-3-sulfonamide

6-chloro-N-(3,5-difluoro-6-methoxypyridin-2-yl)-7-(trifluoromethyl)-1H-indole-3-sulfonamide

N-(4-cyano-2-fluorophenyl)-6-(pyridin-3-yl)-1H-indole-3-sulfonamide

N-(2,1,3-benzothiadiazol-4-yl)-5-iodo-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(4-chloro-2,5-difluorophenyl)-6-(2,2,2-trifluoroethoxy)-1H-indole-3-sulfonamide

6-chloro-N-(2-oxo-2,3-dihydro-1,3-benzoxazol-7-yl)-1H-indole-3-sulfonamide

6-chloro-N-(2,2,6-trifluoro-1,3-benzodioxo1-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(2,4,5-trifluorophenyl)-1H-benzo[g]indole-3-sulfonamide

6-chloro-N-(6-methoxy-2,1,3-benzoxadiazol-5-yl)-1H-indole-3-sulfonamide

N-(2,1,3-benzothiadiazol-5-yl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(4-ethynyl-2-fluorophenyl)-6-methoxy-1 H-indole-3-sulfonamide

6-chloro-N-[3,6-difluoro-5-(2-methoxyethoxy)pyridin-2-yl]-1H-indole-3-sulfonamide

6-chloro-N-[4-(cyclopropylmethoxy)-2,5-difluorophenyl]-1H-indole-3-sulfonamide

N-(4-acetyl-2-fluorophenyl)-6-chloro-1H-indole-3-sulfonamide

6-chloro-N-(4-cyano-3-methoxyphenyl)-1H-indole-3-sulfonamide

6-chloro-N-(3,5-difluoropyridin-2-yl)-1H-indole-3-sulfonamide

6-chloro-N-(6-cyano-2,2-difluoro-1,3-benzodioxo1-4-yl)-1H-indole-3-sulfonamide

N-(4-chloro-2,5-difluorophenyl)-2-fluoro-6-methoxy-1H-indole-3-sulfonamide

N-(4-chloro-2,5-difluorophenyl)-2-fluoro-6-methoxy-1H-indole-3-sulfonamide

6-chloro-N-(2,2-difluoro-1,3-benzodioxo1-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(4-cyano-2-fluorophenyl)-6-phenyl-1 H-indole-3-sulfonamide

N-(1,3-benzodioxo1-4-yl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(4-cyanophenyl)-1-benzothiophene-3-sulfonamide

6-chloro-N-(4-nitrophenyl)-1 H-indole-3-sulfonamide

N-(4-cyanophenyl)-6-(methylsulfinyl)-1H-indole-3-sulfonamide

6-(methylsulfonyl)-N-(2,4,5-trifluorophenyl)-1 H-indole-3-sulfonamide

N-(4-cyanophenyl)-5-iodo-1 H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(2,4,5-trifluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(6-fluoro-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(5-fluoro-1,3-benzothiazol-6-yl)-1H-indole-3-sulfonamide

6-chloro-N-(7-fluoro-2,1,3-benzothiadiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(4-chloro-2,5-difluorophenyl)-6-(thiophen-3-yl)-1H-indole-3-sulfonamide

6-chloro-N-(2,4-difluorophenyl)-1H-indole-3-sulfonamide

6-chloro-N-[3,6-difluoro-5-(3-hydroxypropyl)pyridin-2-yl]-1H-indole-3-sulfonamide

6-chloro-N-(2,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(4-chloro-2-fluorophenyl)-6-methoxy-1 H-indole-3-sulfonamide

6-chloro-N-(5-fluoro-1,1-dioxido-2,3-dihydro-1-benzothiophen-6-yl)-1H-indole-3-sulfonamide

N-(2,2-difluoro-1,3-benzodioxo1-4-yl)-6-(methylsulfonyl)-1H-indole-3-sulfonamide

6-bromo-N-(2,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(3,5-dichloropyridin-2-yl)-1H-indole-3-sulfonamide

6-chloro-N-(6-fluoro-3-oxo-2,3-dihydro-1H-isoindo1-5-yl)-1H-indole-3-sulfonamide

N-(5-bromo-3-methoxypyridin-2-yl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(4-chloro-2-fluorophenyl)-6-cyano-1 H-indole-3-sulfonamide

6-chloro-N-(2,4,5-trifluorophenyl)-1-benzofuran-3-sulfonamide

6-chloro-N-(2,2-difluoro-1,3-benzodioxo1-4-yl)-1-benzofuran-3-sulfonamide

6-chloro-N-(4-cyanophenyl)-1-benzofuran-3-sulfonamide

6-chloro-N-(3-oxo-1,3-dihydro-2-benzofuran-5-yl)-1H-indole-3-sulfonamide

6-chloro-N-(2-cyano-5-fluorophenyl)-1 H-indole-3-sulfonamide

6-chloro-N-(5-chloro-4-methoxypyridin-2-yl)-1 H-indole-3-sulfonamide

6-chloro-N-(3,5-dimethoxypyridin-2-yl)-1 H-indole-3-sulfonamide

6-chloro-N-[5-(difluoromethoxy)-3,6-difluoropyridin-2-yl]-1H-indole-3-sulfonamide

N-(2,1,3-benzothiadiazol-5-yl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide

6-bromo-N[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamide

N-(4-cyano-2,5-difluorophenyl)-1,6,7,8-tetrahydrocyclopenta[g]indole-3-sulfonamide

7-bromo-6-chloro-N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamide

N-(4-cyano-2,5-difluorophenyl)-6-fluoro-1H-indole-3-sulfonamide

N-(4-cyanophenyl)-6-(trifluoromethyl)-1 H-indole-3-sulfonamide

N-(4-cyano-2,5-difluorophenyl)-6-methyl-1 H-indole-3-sulfonamide

6-bromo-N-(2,2-difluoro-1,3-benzodioxo1-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(2,1,3-benzoselenadiazol-5-yl)-6-chloro-1H-indole-3-sulfonamide

N-(4-cyanophenyl)-6-methyl-1H-indole-3-sulfonamide

6-chloro-N-(6-fluoro-2,1,3-benzothiadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

7-bromo-N-(4-cyano-2,5-difluorophenyI)-1H-indole-3-sulfonamide

6-chloro-N-(3,6-difluoro-5-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(2,5-difluoro-4-methylphenyl)-6-(methylsulfinyl)-1H-indole-3-sulfonamide

6-fluoro-N-(6-fluoro-2,1,3-benzothiadiazol-5-yl)-1H-indole-3-sulfonamide

6-chloro-N-(4-cyano-2,5-difluorophenyI)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(4-chloro-2-fluorophenyl)-6-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(2,1,3-benzothiadiazol-4-yl)-6-chloro-7-(trifluoromethyl)-1H-indole-3-sulfonamide

N-(2,1,3-benzothiadiazol-5-yl)-1H-benzo[g]indole-3-sulfonamide

N-(4-cyano-3-fluorophenyI)-1,6,7,8-tetrahydrocyclopenta[g]indole-3-sulfonamide

6-bromo-N-(4-cyanophenyl)-5-methyl-1H-indole-3-sulfonamide

N-(4-cyano-2-fluorophenyI)-4,6-difluoro-1H-indole-3-sulfonamide

N-(4-cyano-2,5-difluorophenyl)-1 H-indole-3-sulfonamide

6-chloro-N-(4-cyano-3-methylphenyI)-1H-indole-3-sulfonamide

N-(4-cyanophenyl)-6-fluoro-1 H-indole-3-sulfonamide

N-(2,1,3-benzothiadiazol-5-yl)-6-fluoro-1H-indole-3-sulfonamide

N-(2,1,3-benzothiadiazol-5-yl)-1,6,7,8-tetrahydrocyclopenta[g]indole-3-sulfonamide

6-chloro-N-[5-(cyanomethyl)-3-fluoro-6-methylpyridin-2-yl]-1H-indole-3-sulfonamide

7-chloro-N-(4-cyano-2,5-difluorophenyI)-1H-indole-3-sulfonamide

6-chloro-N-(4-chloro-2,5-difluorophenyI)-7-(pyridin-2-ylmethoxy)-1H-indole-3-sulfonamide

N-(4-chloro-2-fluorophenyl)-8-(difluoromethyl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

N-(4-cyanophenyl)-5H-[1,3]dioxolo[4,5-t]indole-7-sulfonamide

N-(5-bromo-4-chloro-2-fluorophenyl)-6-chloro-1H-indole-3-sulfonamide

6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-phenoxy-1H-indole-3-sulfonamide

N-(4-cyano-2-fluorophenyl)-6-phenoxy-1 H-indole-3-sulfonamide

6-chloro-N-[4-(2,2-difluoroethoxy)-2-fluorophenyl]-1H-indole-3-sulfonamide

N-(4-chloro-2-fluorophenyl)-5H-[1,3]dioxolo[4,5-f]indole-7-sulfonamide

N-(4-bromo-2-fluoro-5-methylphenyI)-6-chloro-1H-indole-3-sulfonamide

N-(4-chloro-2-fluorophenyl)-6-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

N-(4-cyano-2-fluorophenyl)-6-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-indole-3-sulfonamide

N-(4-cyano-2-fluorophenyl)-6-(pyridin-4-yl)-1H-indole-3-sulfonamide

N-(7-bromo-2,2-difluoro-1,3-benzodioxo1-4-yl)-6-chloro-1H-indole-3-sulfonamide

N-(2,5-difluorophenyI)-5-iodo-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide

6-chloro-N-(2-chloro-3-fluorophenyl)-1H-indole-3-sulfonamide

N-(4-cyano-2,5-difluorophenyI)-4,6-difluoro-1H-indole-3-sulfonamide

N-(4-cyano-2-fluorophenyl)-1 H-indole-3-sulfonamide

N-(5-chloro-3-fluoropyridin-2-yl)-6-methoxy-1 H-indole-3-sulfonamide

N-(4-chloro-2-fluorophenyl)-8-hydroxy-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide

N-(4-cyano-2-fluorophenyl)-6-(tetrahydrofuran-2-ylmethoxy)-1H-indole-3-sulfonamide

N-(2,2-difluoro-1,3-benzodioxo1-5-yl)-6-(methylsulfonyI)-1H-indole-3-sulfonamide

6-(5-chlorothiophen-2-yl)-N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide

6-chloro-N-(2,2,7-trifluoro-1,3-benzodioxo1-4-yl)-1H-indole-3-sulfonamide

6-chloro-7-methoxy-N-(2,4,5-trifluorophenyl)-1 H-indole-3-sulfonamide

6-chloro-N-(4-chloro-2-fluoro-5-methylphenyI)-1H-indole-3-sulfonamide

N-(4-chloro-2-fluorophenyl)-6-fluoro-1 H-indole-3-sulfonamide

N-(4-ethynylphenyl)-6-(methylsulfonyl)-1 H-indole-3-sulfonamide

The compounds of the present invention can be prepared according to themethods disclosed in the experimental section of this application.

Therapeutic and Diagnostic Application

In one aspect, the invention relates to any one of the compoundsdescribed herein, for use in therapy or diagnosis, particularly in thetherapy of animals, most preferably humans.

Because of their GPR17 modulating properties, the compounds of thepresent invention can be used as medicine, and may be used for thetreatment and/or prevention of various diseases of the CNS system.

One embodiment of the present disclosure is thus a compound as describedherein for use as a medicine, in particular for use as a medicine forthe treatment and/or prevention of a GPR17-associated disease, i.e. adisease which is associated with a dysfunction of the GPR17 signalingsystem such as, for example, an overexpression and/or overactivity ofGPR17 receptors. Without wished to be bound by any theory, the activityof GPR17 may be increased, extended or otherwise altered in certaintissues, for example in oligodendrocyte progenitor cells (OPCs) orduring maturation of oligondendrocytes, potentially due to activatingendogeneous stimuli such as, for example, inflammation factors. This mayprevent the differentiation of oligodendrocytes and an efficientmyelination thus promoting the emergence or further development of amyelination disease (see Chen et al, supra). Negative GPR17 modulatorsmay thus promote myelination by decreasing or turning off GPR17 activityand by supporting OPC maturation into myelin-producing oligondendrocytes(see e.g. Simon et al, supra).

In one preferred aspect, the invention relates to any one of thecompounds described herein, for use in therapy or diagnosis for use inthe prevention, or treatment of a disorder or syndrome selected fromand/or associated with a myelination disorder, particularly of thecentral nervous system.

Myelination disorders may be classified in three broad categories:

-   -   demyelination disorders wherein the myelin is initially normal        but is destroyed or degraded for certain reasons,    -   dysmyelination disorders wherein the formed myelin is abnormal        and dysfunctional (e.g. because of mutations affecting the        structure of myelin) and may degenerate, and    -   hypomyelination disorders, which are characterized by abnormal        low amounts of myelin.

An example of a dysmyelination disorder is metachromatic leukodystrophy.

An example of a hypomyelination disorders is Pelizaeus Merzbacherdisease.

A demyelination disorder describes a loss of myelin around axons due tothe damage or degradation of otherwise functioning myelin. The causesfor degradation can be multifold and can be based on e.g. inflammatoryand/or autoimmune processes (such as e.g. multiple sclerosis),infections (such as e.g. progressive multifocal leukoencephalopathycaused by a papovavirus), metabolic disorders (e.g. central pontinemyelinolysis), toxic or mechanic traumata and ischemic states.Demylination disorders may occur in central and peripheral tissues.

Neurodegenerative disorders have been recently associated strongly witha loss of myelination. It is believed that preserved oligodendroglialand myelin functionality is a crucial prerequisite for the prevention ofaxonal and neuronal degeneration (see e.g. Ettle et al, supra). NegativeGPR17 modulators may thus represent an excellent treatment option forany demyelination disorders, including but not limited toneurodegenerative diseases associated with demyelination and/or impactedmyelination such as e.g. ALS, MSA, Alzheimer's disease, HuntingtonDisease or Parkinson's Disease.

In a particularly preferred aspect, the compounds of the presentinvention can thus be used in the prevention and/or treatment of aperipheral or central myelination disorder, preferably of ademyelination disorder, and particularly preferably of a demyelinationdisorder of the central nervous system. In one aspect, the compounds ofthe present invention are used in the treatment and/or prevention and/ordiagnosis of a myelination disorder, preferably a demyelinationdisorder, by oral administration.

Examples of such myelination disorders to be treated and/or prevented bythe presently disclosed compounds are, in particular,

-   -   multiple sclerosis (MS) including its various subforms,    -   neuromyelitis optica (also known as Devic's disease),    -   chronic relapsing inflammatory optic neuritis, acute        disseminated encephalomyelitis,    -   acute haemorrhagic leucoencephalitis (AHL),    -   periventricular leukomalacia    -   demyelination due to viral infections, e.g. by HIV or        progressive multifocal leucoencephalopathy,    -   myelopathies such as e.g. tabes dorsalis (syphilitic myelopathy)    -   central pontine and extrapontine myelinolysis,    -   demyelination due to traumatic brain tissue damage, including        compression-induced demyelination, e.g. by tumors    -   demyelination in response to hypoxia, stroke or ischaemia or        other cardiovascular diseases,    -   demyelination due to exposure to carbon dioxide, cyanide, or        other CNS toxins    -   Schilder's disease,    -   Balo concentric sclerosis,    -   Perinatal encephalopathy,    -   Neurodegenerative Diseases including, in particular,        -   Amyotrophic lateral sclerosis (ALS).        -   Alzheimer's disease (AD).        -   Multiple system atrophy        -   Parkinson's Disease        -   Spinocerebellar ataxia (SCA), also known as spinocerebellar            atrophy        -   Huntington's Disease    -   psychiatric disorders such as schizophrenia and bipolar disorder        (see e.g. Fields, Trends Neurosci 31, 2008, 361; Tkachev et al,        Lancet 362, 2003, 798).    -   peripheral myelination diseases such as leukodystrophies,        peripheral demyelinating neuropathies, Dejerine-Sottas syndrome        or Charcot-Marie-Tooth disease

Moreover, the compounds of the present invention may be used for thetreatment of prevention of the dysfunction of tissues where GPR17 isexpressed such as e.g. heart or kidney, including but not limited totreating or preventing ischaemic disorders of kidney and heart.

The treatment or prevention of a CNS disease such as, in particular, amyelination disease, preferably a demyelination disease, also includesthe treatment of the signs and symptoms associated with such a disease.Hence, the compounds of the present invention may also be used to treata disorder or syndrome associated with brain tissue damage, acerebrovascular disorder, and certain neurodegenerative diseasesunderlying or associated with a demyelination disorder.

In one embodiment, the use of the compounds of the present invention forthe treatment and/or prevention of MS also includes the treatment and/orprevention of the signs and symptoms associated with MS such as negativeeffects on optic nerves (vision loss, double vision), dorsal columns(loss of sensation), corticospinal tract (spastic weakness), cerebellarpathways (incoordination, dysarthria, vertigo, cognitive impairment),medial longitudinal fasciculus (double vision on lateral gaze), spinaltrigeminal tract (face numbness or pain), muscle weakness (impairedswallowing, control of the bladder or gut, spasms), or psychologicaleffects associated with the underlying disease such as depression,anxiety or other mood disorders, general weakness or sleeplessness.

Hence, the compounds of the present invention are for use in treatingsigns and symptoms of a myelination disease, such as multiple sclerosis,wherein such signs and symptoms include but are not limited to the groupof vision loss, vision impairment, double vision, loss or impairment ofsensation, weakness such as spastic weakness, motor incoordination,vertigo, cognitive impairment, face numbness, face pain, impairedswallowing, impaired speech, impaired control of bladder and/or gut,spasms, depression, anxiety, mood disorders, sleeplessness, and fatigue.

In one preferred embodiment, the compounds of the present invention arefor use in treating multiple sclerosis. MS is a heterogeneousmyelination disease and can manifest itself in a variety of differentforms and stages, including but not limited to Relapsing-Remitting MS,Secondary-Progressive MS, Primary Progressive MS, Progressive RelapsingMS, each depending on activity and disease progression.

In another aspect, the compound of the present invention may be used inthe prevention and treatment of a spinal cord injury, perinatalencephalopathy, stroke, ischemia, or a cerebrovascular disorder, or forimproving the recovery following these events.

In one aspect, the invention relates to a method for the preventionand/or treatment of a syndrome or disorder associated with a myelinationdisorder, or with a disorder or syndrome associated with a brain tissuedamage, which comprises administering to a patient in need thereof atherapeutically effective amount of a compound as described herein. Apatient in need of such a treatment can be any patient who sufferedbrain tissue damage such as by mechanical, chemical, viral, or othertrauma.

In one aspect, the invention relates to a method for the preventionand/or treatment of a syndrome or disorder associated with a myelinationdisorder, preferably with a demyelination disorder, or with a disorderor syndrome associated with stroke or other brain ischemia, whichcomprises administering to a patient in need thereof a therapeuticallyeffective amount of a compound as described herein. A patient in needthereof may be any patient that recently experienced a cerebralischemia/stroke which may have been caused, for example, by theocclusion of a cerebral artery either by an embolus or by localthrombosis.

In one aspect, the compounds of the present invention are for use in thetreatment/or prevention of Neuromyelitis optica (also known as Devic'sdisease or Devic's syndrome).

Neuromyelitis optica is a heterogeneous disorder characterized byinflammation and demyelination of the optic nerve and the spinal cord.Many of the associated symptoms are similar to MS and include muscleweakness, in particular of the limbs, reduced sensation and loss ofbladder control.

In one aspect, the compounds of the present invention are for use inpreventing and/or treating ALS. ALS has been associated recently witholigodendrocyte degeneration and increased demyelination, suggesting ALSas a target disease for negative GPR17 modulators (Kang et al, supra;Fumagalli et al, Neuropharmacology 104, 2016, 82).

In one aspect, the compounds of the present invention are for use inprevention and/or treating Huntington Disease. Huntington is welldescribed to be associated with impacted myelination, (Bartzokis et al,supra; Huang et al, Neuron 85, 2015, 1212).

In one aspect, the compounds of the present invention are for use inprevention and/or treating multiple system atrophy. MSA was associatedstrongly with demelination recently (Ettle supra, Jellinger supra)suggesting remyelination strategies to treat or prevent MSA.

In one aspect, the compounds of the present invention are for use inprevention and/or treating Alzheimer's Disease. AD has been recentlyobserved to be associated with increased cell death ofoligodendronecytes and focal demyelination and to represent apathological process in AD (Mitew et al, Acta Neuropathol 119, 2010,567),

One aspect of the present invention relates to a method of treatment ofany one of the diseases or disorders described herein, in particular ofa myelination disease such as MS,

Neuromyeltis optica, ALS or others, by administering to a subject inneed thereof, including a human patient, a therapeutically effectiveamount of a compound of the present invention.

GPR17 has been recently also associated with food uptake, insulincontrol and obesity. According to various reports, negative modulatorsof GPR17 may be helpful for controlling food uptake and for treatingobesity (see e.g. Ren et al, Diabetes 64, 2015; 3670.) Hence, oneembodiment of the present invention relates to the use of the compoundsherein for the prevention and/or treatment of obesity, and methods oftreating obesity.

The treatments according to the present invention may comprise theadministration of one of the presently disclosed compounds as “standalone” treatment of a CNS disease, in particular of a myelinationdisease or disorder such as MS or ALS. Alternatively, a compounddisclosed herein may be administered together with other useful drugs ina combination therapy.

In a non-limiting example, a compound according to the present inventionis combined with another medicament for treating a myelination disease,such as MS, said other medicament having a different mode of action,such as e.g. an anti-inflammatory drug. Likewise, a compound of thepresent invention can be combined with an analgesic drug if a painfulmyelination condition is to be treated. Also, a compound of the presentdisclosure may be used in combination with an antidepressant to co-treatpsychological effects associated with the underlying myelination diseaseto be treated.

In combination therapies, the two or more active principles may beprovided via the same formulation or as a “kit of parts”, i.e. inseparate galenic units to be used in combination. Also, the two or moreactive principles, including the compounds of the present invention, maybe administered to the patient at the same time or subsequently, e.g. inan interval therapy. The additional drug may be administered by the samemode or a different mode of administration. For example, the GPR17modulator of the present invention may be administered orally, while thesecond medicament may be administered by subcutaneous injection.

The second medicament for the treatment of MS may be selected from, forexample, corticosteroids (e.g. prednisone, declamethasone),dalfampridine, interferon beta-1a, interferon beta-1b, glatirameracetate, peginterferon beta-1a, daclizumab, teriflunomide, fingolimod,siponimod, dimethylfumarate, alemtuzumab, mitoxantrone, ocrelizumab,natalizumab and bioequivalents or biosimilars thereof.

In one aspect, the compounds of the present invention may be used forthe diagnosis and/or monitoring of a GPR17- related disease, as furtherdescribed herein, in particular of a demyelinating disease, as disclosedherein, preferably in the diagnosis and monitoring of multiplesclerosis.

In one aspect, the compounds of the present invention can be used todiagnose and/or monitor the expression, distribution and/or activationof the GPR17 receptor either in-vivo, e.g. directly in a subject, suchas using molecular imaging techniques, or in-vitro, such as e.g. byexamining any samples such as body fluids or tissues taken from asubject. Any such determination of the GPR17 activity, expression and/ordistribution may be used to predict, diagnose and/or monitor (a) thestatus and progression of a GPR17-associated disease as describedherein, in particular a myelination disease including but not limitedto, for example, multiple sclerosis, and/or (b) the efficacy and/orapplicability and/or proper dosing of a treatment associated with anysuch GPR17-associated disease.

In one aspect, the compounds of the present invention may be used as PETor SPECT tracers, as further disclosed herein, in order to performin-vivo diagnosis and/or disease monitoring. By this, the expression,activation and/or distribution of a GPR17 receptor may be directlymeasured in a subject, e.g. by imaging of a human patient after theadministration of a GPR17 PET or SPECT tracer of the present invention.This may facilitate a proper diagnosis of the disease, may help todetermine applicable treatment options and/or may be used to monitordisease progression and/or to monitor or predict the success of amedical intervention, including the selection and proper administrationand/or dosing of a therapeutic drug.

Hence, one embodiment of the present invention is the use of a PET orSPECT tracer of the present invention in a diagnostically effectiveamount for the diagnosis of a GPR17-associated disorder, preferably of amyelination disease, including not limited to MS.

One embodiment of the present invention relates to a method ofdiagnosing a GPR17-associated disorder, preferably a myelinationdisorder including but not limited MS, said method including the stepsof (a) administering a PET or SPECT tracer of the present invention in adiagnostically effective amount to a subject (b) determining the amountand/or distribution of GPR17 in the subject by its binding to the PET orSPECT tracer aministered and (c) comparing the results with results of acomparative subject or group of subjects.

In one embodiment, the PET or SPECT tracers of the present invention maybe used in conjunction with a therapeutic drug, i.e. as a CompanionDiagnostic, in order to monitor and/or predict the efficacy and/orsafety of said therapeutic drug in a particular subject, or to estimatea drug's proper dosage.

One embodiment relates to a PET or SPECT tracer of the present inventionfor use as a Companion Drug in conjunction with a therapeutic drug. Thetherapeutic drug to be used with the PET or SPECT tracer of the presentinvention may be selected from the group of (a) an unlabeled compound ofthe present invention, (b) a GPR17 modulating compound which isdifferent from the compounds of the present invention and (c) a drug forthe treatment of a myelination disease, including but not limited to adrug for use in multiple sclerosis treatment, which is not a GPR17modulator.

One embodiment relates to a kit comprising

-   -   (a) as a first component, a PET or SPECT tracer of the present        invention, in particular a PET or PET tracer based on a compound        of the present invention including but not limited to those        having a structure according to any one of Formula I, II, Ila,        Ilb, IIc, Ild, Ile, Ilf, Ill, IIla, IIIb, IIIc, or IV, as        further defined herein, or having a structure of any one of the        compounds disclosed herein, but having incorporated at least one        radionuclide which is suitable for PET or SPECT imaging,        preferably a radionuclide selected from ¹⁸F, ¹¹C, ¹²³I, ¹²⁵I and        ¹³¹I,    -   (b) as a second component, a therapeutic drug selected from        among        -   i. a compound of the present invention including but not            limited to those having a structure according to anyone of            Formula I, II, Ila, Ilb, IIc, Ild, Ile, Ilf, Ill, IIla,            IIIb, IIIc, or IV, as further defined herein, or having a            structure of any one of the individual compounds disclosed            herein, and having no radionuclide incorporated,        -   ii. a GPR17 modulating compound which is different from the            compounds of the present invention as defined in (i), and        -   iii. a drug for the treatment of a myelination disease,            including but not limited to a drug for use in multiple            sclerosis treatment, but having no GPR17 modulating activity

Alternatively, the compounds of the present invention may be used in anin-vitro diagnostic assay, for example for the examination of suitablebody fluids of a subject such as e.g. blood, plasma, urine, saliva, orcerebrospinal fluid for any level of GPR17 expression, activity and/ordistribution.

One embodiment relates to a method of treating a GPR17-associateddisease, in particular a myelination disease, preferably a demyelinationdisorder, including but not limited to multiple sclerosis, wherein saidmethod includes the steps of (a) determining the expression, activityand/or distribution of the GPR17 receptor of a subject, (b) comparingthe expression, activity and/or distribution of the GPR17 receptor insaid subject with the expression, activity and/or distribution of theGPR17 receptor in one or more healthy subjects or a population, (c)determining the need for medical treatment or prophylaxis of saidsubject based on a deviation of expression, activity and/or distributionof GPR17 of said subject from healthy subjects or a population and (d)treating the subject having the deviation of expression, activity and/ordistribution of the GPR17 receptor by administering a therapeutic drugto said individual, which drug is suitable for the treatment ofGPR17-associated diseases or disorders, in particular by administering aGPR17 modulator, preferably by administering one of more of thecompounds of the present invention. In one embodiment, the determination(a) of the expression, activity and/or distribution of GPR17 will beconducted using one of the compounds of the present invention, inparticular with a PET or SPECT tracer of the present invention, or by anin vitro examination of body fluids or tissue of said subject using aPET or SPECT tracer of the present invention.

In one preferred aspect, the invention relates to a pharmaceuticalcomposition comprising a compound as described herein, and apharmaceutical acceptable carrier.

For the administration as a medicinal drug, the compounds may be used inpharmaceutical composition comprising a compound of the presentdisclosure, and a pharmaceutically acceptable carrier, as furtherdefined herein. Such a pharmaceutical composition can be adapted, forexample, for oral, intravenous, intramuscular, subcutaneous, nasal,rectal, buccal or transdermal administration and may comprisepharmaceutically acceptable carriers, adjuvants, diluents, stabilizersand the like.

In one embodiment, the compounds of the present invention may beadministered orally, e.g. in the form of a tablet, a capsule, a dragee,a powder, a granulate, or in form of a liquid or a semi-solid, includinge.g. syrups, suspensions, emulsions or solutions, by way of non-limitingexample.

For instance, the compounds of the present invention may be dissolved inoils, propylene glycol or other solvents which are commonly used toproduce an injection. Suitable examples of the carriers include, but notlimited to, physiological saline, polyethylene glycol, ethanol,vegetable oils, isopropyl myristate, etc. The compounds of the presentinvention may be formulated into injections by dissolving, suspending oremulsifying in water-soluble solvent such as saline and 5% dextrose, orin water-insoluble solvents such as vegetable oils, synthetic fatty acidglyceride, higher fatty acid esters and propylene glycol. Theformulations of the invention may include any of conventional additivessuch as dissolving agents, isotonic agents, suspending agents,emulsifiers, stabilizers and preservatives.

A tablet may provide an immediate release or sustained release of thecompounds of the present invention. oral formulations, such as tablets,may contain, without limitation, sustained release agents,disintegrants, fillers, lubricants, stabilizers, antioxidants, flavours,dispersion agents, electrolytes, buffers, dyes, or conservation agents.Suitable excipients and formulations are known to those skilled in theart and are disclosed in standard monographs such as like Remington(“The science and practice of pharmacy”, Lippincott, Williams & Wilkins,2000).

Non-limiting examples of disintegrants include pregelatinised starch,sodium starch glycolate, microcrystalline cellulose,carboxymethylcellulose sodium (CMC-Na), cross-linked CMC-Na, andlow-substituted hydroxypropylcellulose, as well as mixtures thereof.

Suitable fillers and binders include without limitation microcrystallinecellulose, powdered cellulose, lactose (anhydrous or monohydrate),compressible sugar, starch (e.g. corn starch or potato starch),pregelatinised starch, fructose, sucrose, dextrose, dextrans, othersugars such as mannitol, maltitol, sorbitol, lactitol and saccharose,siliconised microcrystalline cellulose, calcium hydrogen phosphate,calcium hydrogen phosphate dihydrate, dicalciumphosphate dihydrate,tricalciumphophate, calcium lactate or mixtures thereof.

Lubricants, antiadherents and/or glidants include stearic acid,magnesium stearate, calcium stearate, sodium lauryl sulphate,hydrogenated vegetable oil, hydrogenated castor oil, sodium stearylfumarate, macrogols, glycerol dibehenate, talc, corn starch, silicondioxide, and the like, including mixtures.

Typical sustained release agents are for example those that swell uponcontact with water such as polyvinylpyrrolidone, hydroxyethylcellulose,hydroxypropylcellulose, other cellulose ethers, starch, pregelatinisedstarch, polymethacrylate, polyvinylacetate, microcrystalline cellulose,dextrans, and mixtures of these. Other sustained release agents may bethose that can be incorporated in a functional coating, which preventsthe rapid disintegration and/or release of the active ingredient fromthe tablet core. Examples of agents that can be used in a functionalcoating are e.g. acrylic resins, cellulose derivatives such ashydroxypropylmethylcellulose acetate phthalate, hydroxypropylcellulose,or ethylcellulose, vinyl acetate derivatives, polyvinyl pyrrolidone,polyvinyl acetate, shellac, methacrylate polymers or methacrylatecopolymers.

A tablet can, for example, be prepared by mixing at least one compoundof the present invention with at least one non-toxic pharmaceuticallyacceptable excipient, such as e.g. binder, filler/diluents, disintegrantagents, plastisizer, and the like, and an optional solvent (aqueous ornon-aqueous), and by subsequent processing the mixture to a tablet by aprocess including but not limited to dry compression, dry granulation,wet granulation, spray drying, or melt extrusion. A tablet can either beuncoated, or coated by known techniques to either mask the bad taste ofan unpleasant tasting drug, or delay disintegration and absorption ofthe active ingredient in the gastrointestinal tract.

The compound of the present invention may also be formulated forparenteral administration by injection, e.g. by bolus injection orinfusion. The compositions for injection may be provided ready to useand may take such forms as suspensions, solutions, or emulsions in oilyor aqueous vehicles, and may contain excipients such as suspending,stabilising, preserving and/or dispersing agents. Alternatively, theactive ingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water or saline, before use.

For nasal administration or administration by inhalation, the compoundsaccording to the present invention may be conveniently delivered in theform of an aerosol spray presentation for pressurised packs or anebuliser, with the use of a suitable propellant, e.g.dichlorodifluoromethane, fluorotrichloromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

For ophthalmic administration, the compounds for use in the presentinvention may be conveniently formulated as micronized suspensions inisotonic, pH-adjusted sterile saline, either with or without apreservative such as a bactericidal or fungicidal agent, for examplephenylmercuric nitrate, benzylalkonium chloride or chlorhexidineacetate. Alternatively, for ophthalmic administration compounds may beformulated in an ointment such as petrolatum.

For rectal administration, the compounds for use in the presentinvention may be conveniently formulated as suppositories. These can beprepared by mixing the active component with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and so will melt in the rectum to release the activecomponent. Such materials include, for example, cocoa butter, beeswaxand polyethylene glycols.

In one embodiment, the compounds maybe administered transdermally. Thismode of administration prevents the so-called 1st pass effect of oraladministration and moreover allows providing more constant plasma levelswhich is of particular advantage in some instances. The design oftransdermal forms such as ointments or creams or other transdermalsystems such as e.g. patches or electrophoretic devices is generallyknown from the art, see e.g. Prausnitz and Langer, Nat Biotechnology2008, Vol 26.11 p1261; WO 2001/47503; WO2009/000262; WO99/49852.

The preferable dose level of the compounds according to the presentinvention depends upon a variety of factors including the condition andbody weight of the patient, severity of the particular disease, dosageform, and route and period of administration, but may appropriately bechosen by those skilled in the art. In various embodiments, thecompounds are administered in an amount ranging from 0.001 to 10 mg/kgof body weight per day, or from 0.03 to 1 mg/kg of body weight per day.Individual doses may range from about 0.1 to 1000 mg of activeingredient per day, from about 0.2 to 750 mg/day, from about 0.3 to 500mg/day, from 0.5 to 300 mg/day, or from 1 to 100 mg/day. Doses may beadministered once a day, or several times a day, preferably with eachdivided portions.

Another aspect of the present invention is a Kit comprising a medicineor a pharmaceutical composition as described herein, and instructionsfor its use.

DEFINITIONS

Any reference to a compound according to the present invention alsoincludes pharmaceutically acceptable salts, solvates, isotopes andco-crystals of such compounds unless expressly indicated otherwise. The“compounds of the present invention” include the compounds referred toand disclosed in the general Formula I, I-2, II, Ila, Ilb, IIc, Ild,Ile, Ilf, IIg, II-2, II-2a, II-2b, II-2c, II-2d, II-2e, II-2f, II-2g,Ill, IIIc, IIIb, IIIc, III-2, III-2a, III-2b, III-2c, IV, IV-2, V, V-2,VI, VIa, VIb, VIc, VId, Vie, Vlf and Vlg as well as the individualcompounds specifically disclosed in the specification and/or theexperimental part. In any instance where a specific substitution isdefined in relation to the “compounds of the present invention”, it isto be understood that this only refers to those compounds carrying therespective substituent. For example, any definition of R12 in the“compounds of the present invention” of course does not apply tocompounds wherein R12 does not exist per se, such as, for example, incompounds of formula VI and its corresponding subformula.

The term “pharmaceutically acceptable salts” relates to any salts thatthe compounds of the present invention may form and which are suitablefor administration to subjects, in particular human subjects. Such saltsinclude but are not limited to acid addition salts, formed either withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like, or formed with organicacids such as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 4-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]oct-2-ene-1-6arboxyic acid, glucoheptonicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, lauryl sulfuric acid, gluconic acid, glutamic acid,hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.Other salts include 2,2-dichloroacetate, adipate, alginate, ascorbate,aspartate, 2-acetamidobenzoate, caproate, caprate, camphorate,cyclamate, laurylsulfate, edisilate, esylate, isethionate, formate,galactarate, gentisate, gluceptate, glucuronate, oxoglutarate,hippurate, lactobionate, napadisilate, xinafoate, nicotinate, oleate,orotate, oxalate, palmitate, embonate, pidolate, p-aminosalicylate,sebacate, tannate, rhodanide, undecylenate, and the like; or saltsformed when an acidic proton present in the parent compound is replaced,such as with ammonia, arginine, benethamine, benzathine, calcium,choline, deanol, diethanolamine, diethylamine, ethanolamine,ethylendiamine, meglumine, glycine, hydrabamine, imidazole, lysine,magnesium, hydroxyethylmorpholine, piperazine, potassium, epolamine,sodium, trolamine, tromethamine or zinc.

The present invention includes within its scope solvates of thecompounds as defined herein. “Solvates” are crystals formed by an activecompound and a second component (solvent) which, in isolated form, isliquid at room temperature. Such solvates may be formed with commonorganic solvents, e.g. hydrocarbon solvents such as benzene or toluene;chlorinated solvents such as chloroform or dichloromethane; alcoholicsolvents such as methanol, ethanol or isopropanol; ethereal solventssuch as diethyl ether or tetrahydrofuran; or ester solvents such asethyl acetate. Alternatively, the solvates of the compounds herein maybe formed with water, in which case they will be hydrates.

The present invention also includes co-crystals within its scope. Theterm “co-crystal” is used to describe the situation where neutralmolecular components are present within a crystalline compound in adefinite stoichiometric ratio. The preparation of pharmaceuticalco-crystals enables modifications to be made to the crystalline form ofan active pharmaceutical ingredient, which in turn can alter itsphysicochemical properties without compromising its intended biologicalactivity. Examples of co-crystal formers, which may be present in theco-crystal alongside the active pharmaceutical ingredient, includeL-ascorbic acid, citric acid, glutaric acid, cinnamic acid, mandelicacid, urea and nicotinamide.

The invention also includes all suitable isotopic variations of acompound of the invention.

An isotopic variation of a compound of the invention is defined as onein which at least one atom is replaced by an atom having the same atomicnumber but an atomic mass different from the atomic mass usually foundin nature with the more abundant isotope(s) being preferred. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, sulphur, fluoroand chloro such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³⁵S, ¹⁸F, and³⁶Cl, respectively. It is to be understood that for any isotop that ispresent in measurable amounts in nature, like e.g. deuterium, the amountof the corresponding radionuclide that may be introduced into thecompounds of the present invention to modulate its properties, willadvantageously exceed its natural abundance in nature. Hence, forexample, the rate of deuterium introduced in the deuterated compounds ofthe present invention is typically higher than the amount of deuteriumto be naturally expected in said compound. Certain isotopic variationsof the invention, for example, those in which a radioactive isotope suchas ³H or ¹⁴C is incorporated, are useful in drug and/or substrate tissuedistribution studies. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with isotopes such as deuterium,i.e., ²H, may afford certain therapeutic advantages resulting formgreater metabolic stability, for example, increased in vivo half-life,reduced dosage requirements and hence may be preferred in somecircumstances. Isotopic variations of the compounds of the invention cangenerally be prepared by conventional procedures using appropriateisotopic variations of suitable reagents.

Also part of the invention are those compounds wherein at least one atomhas been replaced by a radioisotope (radionuclide) of the same or adifferent atom that can be used in vivo imaging techniques such assingle-photon emission computed tomography (SPECT), positron emissiontomography (PET), magnetic resonance spectroscopy (MRS) or magneticresonance imaging (MRI).

Examples for such radioactive GPR17 modulator derivatives usable inSPECT studies (such compounds herein “SPECT tracers”) are compoundswherein a ^(99m)Tc, ¹¹¹In, 82Rb, ¹³⁷Cs, ¹²³I, ¹²⁵I, ¹³¹I, ⁶⁷Ga, ¹⁹²Ir or²⁰¹TI, and preferably ¹²³I has been introduced. For example, in orderfor the compounds of the present invention to be used as SPECT tracers,a ¹²³I isotope may be introduced into a GPR17 modulator as disclosedherein. By way of a non-limiting example, in order for a compound to beused as SPECT tracer, a radionuclide selected from ¹²³I, ¹²⁵I and ¹³¹I,preferably ¹²³I, may be introduced into a compound of the presentinvention. In one embodiment, a SPECT tracer of the present inventionmay be based on the structure of a iodine-containing GPR17 modulatordisclosed herein, wherein one of the radionuclides ¹²³I, ¹²⁵I and ¹³¹ I,preferably ¹²³I, has been introduced into the position of the iodineatom.

Accordingly, the term “SPECT tracer of the present invention”, relatesto compounds of the present invention including those having a structureaccording to any one of Formula I, I-2, II, Ila, Ilb, IIc, Ild, Ile,Ilf, IIg, II-2, 11-2a, II-2b, II-2c, II-2d, II-2e, II-2f, II-2g, Ill,Illa,IIIb, IIIc, III-2, III-2a, III-2b, III-2c, IV, IV-2, V, V-2, VI,VIa, VIb, VIc, VId, VIe, VIf and VIg as further defined herein, or asotherwise individually disclosed herein, wherein at least oneradioisotope has been introduced in an amount which is suitable forSPECT imaging. This includes but is not limited to ^(99m)Tc, ¹¹¹In,⁸²Rb, ¹³⁷Cs, ¹²³I, ¹²⁵l, ¹³¹l, ⁶⁷Ga, ¹⁹² 1R or ²⁰¹TI, and is preferably¹²³I.

Examples for GPR17 modulator derivatives usable in PET applications(herein “PET tracers”) are compounds wherein ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ⁷⁶Br or¹²⁴l have been introduced. For example, in order for a compound to beused as a PET tracer, an ¹⁸F isotope may be introduced into a compoundof the present invention in an amount which is suitable for PET imaging.In one embodiment, a PET tracer may be based on the structure of afluoro-containing GPR1 7 modulator disclosed herein, wherein therespective radionuclide¹⁸F has been introduced into the position of thefluoro atom. In another embodiment, an ¹⁸F isotope may be introducedinto a compound of the present invention instead of a hydroxy group.This likewise applies to the introduction of at least one ¹¹C, ¹³N, ¹⁵O,⁷⁶Br or ¹²⁴I, instead of an “unlabelled” carbon, nitrogen, oxygen,bromine, or iodine atom, respectively, or instead of any other atom orgroup which may be found suitable for replacement by the respectiveradionuclide. (see e.g. Pimlott and Sutherland, Chem Soc Rev 2011, 40,149).

Accordingly, the term “PET tracer of the present invention”, relates tocompounds as described in the present patent application and having astructure according to any one of the compounds of the present inventionincluding those of Formula Formula I, I-2, II, Ila, Ilb, IIc, Ild, Ile,Ilf, 11g, II-2, II-2a, II-2b, II-2c, II-2d, II-2e, II-2f, II-2g, Ill,Illa, IIIb, IIIc, III-2, III-2a, III-2b, III-2c, IV, IV-2, V, V-2, VI,VIa, VIb, VIc, VId, VIe, VIf and VIg as further defined herein, or asotherwise individually disclosed herein, wherein at least oneradioisotope has been introduced which is suitable for PET imaging. Thisincludes but is not limited to ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ⁷⁶Br or ¹²⁴l, and ispreferably ¹⁸F.

Compounds for use in MRI and MRS are preferably compounds of the presentinvention having a suitable amount of a magnetic radioisotopeincorporated. Those include ¹³C, ¹H, ¹⁸F, ¹⁹F. ¹⁴N, ¹⁷O, ³¹P, and ³³S,wherein ¹⁹F or ¹³C are preferred.

The present invention includes within its scope prodrugs of thecompounds of the present invention. In general, such prodrugs will befunctional derivatives of the compounds described herein which arereadily convertible in vivo, e.g. by endogenous enzymes in the gut orthe blood, into the required GPR1 7 modulating compounds describedherein.

Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985. For example, a prodrug may have asuitable ester group incorporated which will be cleaved by esterases torelease an active GPR1 7 antagonist according to the present invention.

Depending on its substitution pattern, the compounds of the presentinvention may or may not have one or more optical stereocenters, and mayor may not exist as different enantiomers or diastereomers. Any suchenantiomers, diastereomers or other optical isomers are encompassed bythe scope of the invention.

The compound of the present invention may also exist in differentcrystal forms, i.e. as polymorphs, all of which are encompassed by thepresent invention.

The compounds of the present invention may be included in apharmaceutical composition which may also include a pharmaceuticallyacceptable carrier.

“Pharmaceutically acceptable carrier” refers to a diluent, adjuvant,excipient, or carrier, or other ingredient with which a compound of theinvention is administered and which a person of skilled in the art wouldunderstand to be pharmaceutically acceptable but whitself is typicallynot biodynamically active.

The compounds of the present invention are useful in the preventionand/or treatment of certain diseases or disorders in animals, inparticular in humans, as described herein.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i. e., causing at least one of the clinicalsymptoms of the disease not to develop in a subject, in particular ahuman subject, that may be exposed to or predisposed to the disease butdoes not yet experience or display symptoms of the disease).

“Treating” or “treatment” of any disease or disorder includes, in oneembodiment, to improve the disease or disorder (i. e., arresting orreducing the development of the disease or at least reducing one of theclinical symptoms of the disease). In another embodiment “treating” or“treatment” refers to improve at least one physical parameter, which mayor may not be discernible by the subject, in particular a human subject,but which is based on or associated with the disease or disorder to betreated. In yet another embodiment, “treating” or “treatment” refers tomodulating the disease or disorder, either physically (e. g.stabilization of a discernible on non-discernible symptom),physiologically (e. g. stabilization of a physiological parameter), orboth. In yet another embodiment, “treating” or “treatment” refers todelaying the onset or progression of the disease or disorder.Accordingly, “treating” or “treatment” includes any causal treatment ofthe underlying disease or disorder (i.e. disease modification), as wellas any treatment of signs and symptoms of the disease or disorder(whether with or without disease modification), as well as anyalleviation or amelioration of the disease or disorder, or its signs andsymptoms.

“Diagnosis”, “diagnoses” or “diagnosing” of a disease or disorderinclude, in one embodiment, the identification and measurement of signsand symptoms which are associated with said disease. “Diagnosis”,“diagnoses” or “diagnosing” include but are not limited to the detectionand/or measurement of decreased, increased, or otherwise incorrectly(e.g. as to time or place) expressed, activated, or distributed GPR17receptors as indicator of a GPR17-related disease or disorder, ascompared to healthy subjects. In one example, GPR17 ligands may be usedin the form of PET or SPECT tracers for such a diagnosis, including adiagnosis of a myelination disease.

The terms “disease(s)” and “disorder(s)”are used largely interchangeablyherein.

“Monitoring”refers to the observation of a disease, condition or atleast one medical parameter over a certain period of time. “Monitoring”also includes the observations of the effects of a therapeutic drug withthe assistance of a “Companion Drug”

“Companion Diagnostic” as used herein refers to a compound that can beused in conjunction to a therapeutic drug with the aim to determine theapplicability (e.g. in terms of safety and efficacy) of said therapeuticdrug to a specific patient. The use of a “Companion Diagnostic” mayinclude diagnostic and monitoring steps.

The term “animal(s)” and “subject(s)” includes humans. The terms“human,” “patient” and “human subject” are used interchangeably herein.

The invention also relates to methods of treating an animal disease ordisorder, as described in more detail herein, in particular a humandisease or disorder, which includes the administration of the compoundsof the present invention in therapeutically effective amounts.“Therapeutically effective amount” means the amount of a compound that,when administered to a subject, in particular a human subject, fortreating a disease, is sufficient to effect such treatment for thedisease. The “therapeutically effective amount” can vary depending onthe compound, the disease and its severity, and the condition, age,weight, gender etc. of the subject, in particular a human subject, to betreated.

“Diagnostically effective amount” means the amount of a compound that,when administered to a subject, in particular a human subject, fordiagnosing a disease, is sufficient to effect such diagnosis for thedisease.

The term “multiple sclerosis” as used herein refers to the disease asclassified in Section G35 of the 2016/7 ICD-10-CM diagnosis code.

The term “myelination disorder” includes demyelination disorders,dysmyelination disorders and hypomyelination disorders, as furtherdescribed herein. A preferred subclass of myelination disorder for thetreatment with or diagnosis by the compounds of the present inventionare demyelination disorders, particularly of the central nervous system.A particularly preferred myelination disorder for treatment with ordiagnosis by the compounds of the present invention is multiplesclerosis.

The term “GPR17 modulators” as used herein are meant to describecompounds that are capable of modulating the activity of the GPR17receptor, in particular compounds that are capable of decreasing theGPR17 activity. Such “negative GPR17 modulators” include GPR17antagonists which are capable of blocking the effects of GPR17 agonists,as well as GPR17 inverse agonists which are also capable of inhibitingconstitutional active GPR17 receptors or receptor variants.

Whenever numbers appear in subscript following a “C”, these numbers(whether in brackets or not) refer to the range of carbon atomscomprised by the respective group directly following the numbers. Forexample, “C₁₋₆” and “(C₁₋₆)” both refer to a group, as further specifiedherein, which comprises from 1 to 6 C-Atoms.

“Alkyl” includes saturated aliphatic hydrocarbyl groups. The hydrocarbonchain may be either straight-chained or branched. Examples of “alkyl”include those with 1-6 carbon atoms (“C₁₋₆alkyl”), those with 1-5 carbonatoms (“C₁₋₅ alkyl”), 1-4 carbon atoms (“C₁₋₄ alkyl”), or only 1-3carbon atoms (“C₁₋₃ alkyl”). This term is exemplified by groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, t-amyl, and the like. Any numbers of C atoms in alkyls orother groups may be indicated herein in brackets or without brackets.

“Alkenyl” includes monovalent aliphatic hydrocarbyl groups comprising atleast one double bond. Alkenyls may be branched or straight-chained.Examples of “alkenyl” include those with 2-3 carbon atoms (“C₂₋₃alkenyl”) or 2-6 carbon atoms (“C₂₋₆ alkenyl”). This term is exemplifiedby groups such as vinyl (ethenyl), allyl or butenyl. The term “propenyl”refers to alkenyls with three chain forming carbon atoms and includeslinear (n-propenyl) as well as branched (isopropenyl/methylethenyl)groups.

“Alkynyl” includes monovalent aliphatic hydrocarbyl groups comprising atleast one triple bond. Alkynyls may be branched or straight-chained.Examples of “alkynyl” include those with 2-6 carbon atoms(“C₂₋₆alkynyl”).This term is exemplified by groups such as ethynyl,propargyl and 2-butynyl.

“Alkyloxy” and “alkoxy”, as used interchangeably herein (togetheralk(yl)oxy), include the group —OR wherein R is “alkyl” as defined andexemplified further herein. Particular alk(yl)oxy groups include, by wayof example, meth(yl)oxy, eth(yl)oxy, n-prop(yl)oxy, isoprop(yl)oxy,n-but(yl)oxy, tert-but(yl)oxy, sec-but(yl)oxy, isobut(yl)oxy,n-pent(yl)oxy, 1,2-dimethylbut(yl)oxy, and the like.

“Halogen” includes fluoro, chloro, bromine, and iodine atoms.

“Azido” refers to the group —N═N═N.

“Cyanomethyl” refers to —CH₂—≡CN.

The term “haloalkyl” as used herein refers to an “alkyl” as describedherein (and wherein the numbers indicate the numbers of C-atoms in thealkyl part), which is substituted with one or more halogen atoms.Representative examples of “halo(C₁₋₃)alkyl” groups include, but are notlimited to —CF₃, —CCI₃, —CFCl₂, —CH₂CH₂CF₃ and —CH₂CF₃.

The term “fluorinated” refers to a group wherein one or more hydrogensare replaced with fluoros. For example, an alkyl or alkoxy group,respectively, which is said to be unsubstituted or fluorinated comprisesa “fluoroalkyl”or “fluoroalk(yl)oxy”, respectively, as defined herein.Likewise, a fluorinated alkoxyalkyl group comprises the groupsfluoroalkoxyalkyl and alkoxyfluoroalkyl.

The term “fluoroalkyl” as used refers to an “alkyl” as described herein,which is substituted with one or more fluoro atoms. Representativeexamples of fluoro(C₁₋₃)alkyl groups include, but are not limited to—CF₃, —CH₂CHF₂ and —CH₂CF₃. Preferred “fluoroalkyl” groups are thosewherein terminal methyl groups are substituted with one or more fluoroatoms; hence, a particularly preferred monofluoroethyl group is—CH²CH₂F, a particularly preferred difluoroethyl group is the group—CH₂CHF₂, a particularly preferred trifluoroethyl group is the group—CH₂CF₃, a particularly preferred monofluoropropyl group is —CH₂CH₂CH₂F,a particularly preferred difluoropropyl is —CH₂CH₂CHF₂, and , aparticularly preferred trifluoropropyl group is —CH₂CH₂CF₃.

The term “mono-, di- and trifluoro” as prefix to chemical groups such asalkyl or alkoxy represents an abbreviation of the respective fluorinatedgroups. For example, the term “mono-, di- and trifluoroethyl”refers tothe group of monofluoroethyl, difluoroethyl and trifluoroethyl.

The term “haloalk(yl) oxy” as used herein refers to an “alk(yl)oxy” asdescribed herein, which is substituted with one or more halogen atoms.Representative examples of halo(C₁₋₃)alkyloxy groups include, but arenot limited to, —OCF₃, —OCCI₃, —OCFCl₂, and —OCH₂CF₃.

The terms “fluoroalkyloxy” or “fluoroalkoxy” as interchangeably usedherein refer to an “alk(yl)oxy” as described herein, which issubstituted with one or more fluoro atoms. Representative examples offluoro(C₁₋₃)alk(yl)oxy groups include, but are not limited to —OCF₃,—OCH₂CHF₂ and —OCF₂CHF₂. A preferred “monofluoroethoxy”group is thegroup —OCH₂CH₂F. A preferred difluoroethoxy is the group —OCH₂CHF₂. Apreferred trifluoroethoxy group is the group —OCH₂CF₃. A preferredmonofluoropropyloxy group is the group —OCH₂CH₂CH₂F. A preferreddifluoropropyloxy group is the group —OCH₂CH₂CHF₂, and a preferredtrifluoropropyloxy group is the group —OCH₂CH₂CF₃.

The term “fluoroalk(yl)oxyalkyl” or “fluoroalkoxyalkyl” asinterchangeably used herein refers to a group comprising an alkyl groupwhich is substituted with an alk(yl)oxy group, wherein the terminalalkoxy group is substituted with one or more fluoro atoms.

Representative examples include, but are not limited to —CH₂CH₂OCF₃,—CH₂OCF₂CH₃, and —CH₂OCHFCHF₂.

The term “fluoroalkyloxyalkyloxy” or “fluoroalkoxyalkoxy” asinterchangeably used herein refers to a group, wherein an alkoxy groupis substituted with another alkoxy group, wherein the terminal alkoxygroup is substituted with one or more fluoro atoms.

Representative examples include, but are not limited to —OCH²OCH₂CF₃,—OCH₂OCF₂CH₃, and —OCH₂CH₂OCHF₂.

“Alkylcarbonyl” refers to the group —C(═O)-alkyl, wherein alkyl is asdefined herein. Typical examples are C₁₋₆ alkylcarbonyl and C₁₋₃alkylcarbonyl, and in particular acetyl (—C(═O)CH₃).

“Alk(yl)oxycarbonyl” refers to the radical —C(═O)—O-alkyl, wherein thealkyl group is as defined herein. Typical examples areC₁₋₆salkoxycarbonyl and C₁₋₃alkoxycarbonyl, and in particularmethoxycarbonyl (—C(═O)OCH₃).

“Alkylsulfiny” refers to the radical —S(═O)-alkyl wherein alkyl is asdefined herein. A typical example is C₁₋₃ alkylsulfinyl, and inparticular methylsulfinyl (—S(═O)CH₃).

“Alkylsulfonyf” refers to the radical —S(═O)₂-alkyl wherein alkyl is asdefined herein. A typical example is C₁₋₃ alkylsulfonyl, and inparticular methylsulfonyl (—S(═O)₂CH₃).

“C₁₋₃ alkoxy(C₁₋₃)alkyl” refers to the group —C₁₋₃ alkyl —O—(C₁₋₃)alkyl,wherein alkyl is as defined herein

“C₁₋₃alkoxy(C₁₋₃)alkoxy” refers to the group —O—C₁₋₃ alkyl—O—(C₁₋₃)alkyl, wherein alkyl is as defined herein

The term “cycloalkyl” as used herein refers to a monovalent groupderived from a saturated hydrocarbon, which may be unsubstituted orsubstituted with one or more substituents as further indicated herein.The “cycloalkyl” is comprised of at least three up to, for example, 7ring forming carbon atoms (“C₃₋₇ cycloalkyl”), or 6 ring forming atoms(“C₃₋₆ cycloalkyl”). Suitable cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyls arepreferably monocyclic but may also include bridged bicyclic groups like,e.g. norbornanyl. A cycloalkyl group may be a terminal group that may bebound to e.g. a ring system via a methylene or methoxy group, in whichcase it would be called “cyclopropylmethyl” or “cyclopropylmethoxy”,respectively. Alternatively, a cyclopropyl group may be substituted, forexample, via a terminal alkoxy or alkoxycarbonyl group, in which case itis called “alkoxycyclopropyl” or “alkoxycarbonylcyclopropyl” group. Forexample, an “ethoxycarbonylcyclopropyl” has the structureCH₃CH₂—O−C(=═)-cyclopropyl-, whereas a cyclopropylmethoxy group has thestructure cyclopropyl-CH₂—O—.

The term “C₃₋₇ cycloalkenyl” as used herein refers to monovalent groupsof 3 to 7 carbon atoms derived from a hydrocarbon which includes atleast one double bond.

The term “heterocycloalkyl” as used herein refers to saturated ringcontaining at least two ring forming carbon atoms and at least one ringforming heteroatom preferably selected from oxygen, sulphur andnitrogen, wherein each ring which may be unsubstituted or furthersubstituted with one or more substituents as described herein. Suitableheterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl,dioxolanyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl,imidazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxazepanyl,diazepanyl, thiadiazepanyl and azocanyl. The term “C₃₋₇heterocycloalkyl” refers to a heterocycoalkyl comprising between threeto seven ring forming atoms. Heterocycloalkyls are preferably monocyclicbut may also include bridged bicyclic moleculs like, e.g. tropanyl.

The term “heterocycloalkenyl” as used herein refers to rings containingat least one double bond, at least two ring forming carbon atoms and atleast one ring-forming heteroatom preferably selected from oxygen,sulphur and nitrogen, wherein each ring which may be unsubstituted orsubstituted with one or more substituents as further defined herein.Suitable heterocycloalkenyl groups include thiazolinyl, isothiazolinyl,imidazolinyl, dihydrofuranyl, dihydropyranyl, and dihydrothiopyranyl.The term “C₃₋₇ heterocycloalkenyl” refers to a heterocycoalkenylcomprising between three to seven ring forming atoms.Heterocycloalkenyls herein are preferably monocyclic.

The term “heteroaryl” as used herein refers to monovalent aromaticgroups containing at least five ring-forming atoms derived from a singlering with e.g. up to six atoms (e.g. “C₅₋₆ heteroaryl”) or multiplecondensed rings with e.g. up to 10 ring forming atoms (e.g. “C₅₋₁₀heteroaryl”), wherein one or more carbon atoms have been replaced by oneor more heteroatoms preferably selected from oxygen, sulphur andnitrogen. Suitable heteroaryl groups include furyl, benzofuryl, thienyl,benzothienyl, thieno[2,3-c]pyrazolyl, pyrrolyl, indolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c ]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrazolyl, pyrazolo[1 ,5-a ]pyridinyl,pyrazolo[3,4-d]pyrimidinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl,oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl,benzoxadiazolyl, benzoselenathiazolyl, isothiazolyl, imidazolyl,benzimidazolyl, imidazo[2, 1-b]thiazolyl, imidazo[1 ,2-a]pyridinyl,imidazo[4,5-b]pyridinyl, purinyl, imidazo[1,2-a]pyrimidinyl,imidazo[1,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl,[1,2,4]triazolo[1,5-a]-5-pyrimidinyl, benzotriazolyl, tetrazolyl,pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, cinnolinyl,phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl,pteridinyl, and triazinyl. As indicated above, the term “C₅₋₆heteroaryl” refers to a heteroaryl with 5-or 6-ring forming atomsalthough some of the ring forming atoms are no carbon atoms butheteroatoms.

The term “C₈₋₁₀ heterocyclyl” as used herein refers to bicyclic groupscontaining 8 to 10 ring-forming atoms, wherein one or more ring formingcarbon atoms have been replaced by one or more heteroatoms preferablyselected from oxygen, sulphur and nitrogen, and wherein one of saidrings is aromatic, and the other one is non-aromatic. Suitable C8-10heterocyclyl are benzodioxolyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,tetrahydroquinoxaline, and the like.

The terms “C₃₋₇cycloalkyl(C₁₋₆)alkyl” or C₃₋₇heterocycloalkyl(C₁₋₆)alkyl refer to a terminal “C₃₋₇cycloalkyl” or“C₃₋₇heterocycloalkyl”, respectively, as defined herein, which areattached to C₁₋₆ alkyl as defined herein.

The terms “C₃₋₇cycloalkyl(C₁₋₆)alkoxy” orC₃₋₇heterocycloalkyl(C₁₋₆)alkoxy” refer to a terminal “C₃₋₇cycloalkyl”or “C₃₋₇heterocycloalkyl”, respectively, as defined herein, which areattached to a “C₁₋₆ alkoxy” as defined herein.

The term “phenyl(C₁₋₆)alkyl” refers to a C₁₋₆alkyl as defined herein,substituted with a phenyl. Examples are benzyl or phenylethyl.

“Phenyl(C₁₋₆)alkoxy” refers to a “C₁₋₆alkyloxy” group substituted with aphenyl. Examples of phenylalkyloxy groups are phenylethyloxy and, inparticular, benzyloxy.

The terms “pyridyl” and “pyridinyl” are used interchangeably herein.

The term “isoxazo” refers to 1,2 oxazol.

The present disclosure is further illustrated by the followingnon-limiting items:

-   -   1. A compound having a structure according to Formula I:

wherein

X1 is N or C(R7),

X2 is NH or O,

X3 is N or C(R12),

R4 is selected from hydrogen and fluoro,

R5 is selected from hydrogen, halogen, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₃alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃akylsulfinyl, andC₁₋₃akylsulfonyl, wherein each alkyl or alkoxy may optionally besubstituted one or more times selected from halogen, C₁₋₃alkoxy, C₂₋₃alkynyl, C₂₋₃ alkenyl, cyano, azido, hydroxyl, amino, and C₁₋₃alkylamino or R5 forms a ring together with R6 as described herein,

R6 is selected from hydrogen, hydroxy, halogen, cyano, azido, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, C₃₋₆cycloalkenyl, C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl, phenyl,C₅₋₁₀ heteroaryl, C₈₋₁₀ heterocyclyl , —ORx, —SRx, —SORx, SO₂Rx,-pentafluorosulfanyl, NRyRzz, —NRyCORx,—NRyCO₂Rx, —NRxCONRyRz, —CORx,—CO₂Rx,—CONRyRz, wherein each alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, heterocycloalkyl, cycloalkenyl, phenyl, heteroaryl orheterocyclyl group in R6 can be unsubstituted or substituted with one ormore substituents preferably selected from halogen, hydroxyl, oxo,cyano, azido, nitro, C₁₋₆ alkyl, C₁₋₆alkoxy(C₁₋₃)alkyl , C₃₋₇cycloalkyl, C₃₋₇ heterocycloalkyl, phenyl, C₅₋₁₀ (preferably C₅₋₆)heteroaryl, ORx, —SRx, —SORx, SO₂Rx, -pentafluorosulfanyl, NRyRz,—NRyCORx,—NRyCO₂Rx, —CORx, —CO₂Rx,—CON RyRz,

-   -   wherein Rx, Ry, Rz and Rzz are independently selected from        hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ cycloalkenyl, C₃₋₇        cycloalkyl(C₁₋₆)alkyl, phenyl, phenyl(C₁₋₆)alkyl, C₃₋₇        heterocycloalkyl, C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl, C₅₋₆        heteroaryl or heteroaryl(C₁₋₆)alkyl, any of which groups can be        unsubstituted or substituted with one or more substituents, or        Ry and Rz, or Ry and Rzz together with the amino atom to which        they are both attached may form an aromatic or nonaromatic,        unsubstituted or substituted C₅₋₆ heterocycle, and wherein Rzz        is different from hydrogen,

or R6 forms together with R7 and the carbon atoms to which R6 and R7 areattached, an unsubstituted or substituted phenyl, unsubstituted orsubstituted pyridyl, unsubstituted or substituted cyclopentyl orunsubstituted or substituted cyclohexyl, wherein each substitution, ifpresent, is selected from halogen, C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl(C₁₋₃) alkyl, C₃₋₇ heterocycloalkyl(C₁₋₃)alkyl, C₁₋₃ alkoxy,and C₁₋₃ alkoxy(C₁₋₃) alkyl, wherein each alkyl or alkoxy can beunsubstituted or substituted with one or more substituents selected fromhalogen and C₁₋₃ alkoxy,

or R6 forms together with R5 and the carbon atoms to which R6 and R5 areattached, a 1,3-dioxolane which may be unsubstituted or substituted withone or two substituents selected from fluoro and methyl, or

R7 is selected from H, halogen, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆alkynyl, C₂₋₆ alkenyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₃₋₇ cycloalkyl, C₃₋₇heterocycloalkyl, phenyl, C₅₋₆ heteroaryl, wherein each alkyl, alkenyl,alkynyl or alkoxy group can be unsubstituted or substituted with one ormore substituents selected from halogen, and C₁₋₆ alkoxy,

R8 is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, and halogen,wherein each alkyl or alkoxy can be unsubstituted or substituted withone or more substituents selected from halogen and C₁₋₃ alkoxy, or formsa ring system together with R9, as described herein,

R9 is selected from hydrogen, halogen, cyano, azido, C₁₋₆ alkyl, C₁₋₆alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and halogen, wherein each alkyl oralkoxy can be unsubstituted or substituted with one or more substituentsselected from halogen and C₁₋₃ alkoxy, or R9 forms together with R8 orR10 and the ring to which they are attached are preferably selected froma bicyclic ring system selected from (a) 2,1,3-benzothiadiazole, (b)2,1,3-benzoselenadiazole, (c) 2,1,3-benzoxadiazole, (d)1,3-benzothiazole, (e) 1,3-benzoxazole which may be unsubstituted or maybe partially hydrogenated and unsubstituted or substituted with oxo, (f)1,3-benzodioxole which may be unsubstituted or substituted with one ortwo substituents selected from fluoro and methyl, (g) benzothiophene,which may be unsubstituted or may be partially hydrogenated andunsubstituted or substituted with one or two substituents selected fromoxo, methyl or fluoro, or (h) benzofuran, which may be unsubstituted ormay be partially hydrogenated and unsubstituted or substituted with oneor two groups selected from oxo, fluoro and methyl, preferably with oneoxo group,

R10 is selected from hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, cyano, cyano(C₁₋₆) alkyl, C₁₋₆ alkylcarbonyl,C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, azido,pentafluorosulfanyl, and nitro, wherein each alkyl, alkenyl, alkynyl oralkoxy can be unsubstituted or substituted with one or more substituentsselected from halogen and C₁₋₆ alkoxy, or R10 forms a ring systemtogether with R9, as described herein,

R11 is selected from hydrogen, halogen, cyano, azido, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylsulfonyl, andC₁₋₆ alkylsulfinyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein each alkylor alkoxy can be unsubstituted or substituted with one or moresubstituents selected from halogen and C₁₋₃alkoxy,

R12 is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy and halogen,wherein each alkyl or alkoxy can be unsubstituted or substituted withone or more substituents selected from halogen and C₁₋₃alkoxy,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

2) A compound according to item 1,

wherein

R4 is hydrogen

R5 is selected from hydrogen, halogen, cyano, C₁₋₃ alkyl, C₁₋₃ alkoxy,C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkylsulfinyl, and C₁₋₃akylsulfonyl, wherein each alkyl or alkoxy may optionally be substitutedone or more times with a substituent selected from halogen, C₁₋₃alkoxy,cyano, azido, and an optionally alkylated amino group, or R5 forms aring together with R6 as described below,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido,unsubstituted or substituted C₁₋₃alkyl, unsubstituted or substitutedC₁₋₃alkoxy unsubstituted or substituted C₂₋₃ alkenyl, unsubstituted orsubstituted C₂₋₃ alkynyl, unsubstituted or substituted C1-3alkylcarbonyl, unsubstituted or substituted C₁₋₃ alkoxycarbonyl,unsubstituted or substituted C₁₋₃alkylsulfinyl, unsubstituted orsubstituted C₁₋₃alkylsulfonyl, unsubstituted or substituted C₃₋₇cycloalkyl, unsubstituted or substituted C₃₋₇ cycloalkyl(C₁₋₃)alkylunsubstituted or substituted C₃₋₇ heterocycloalkyl unsubstituted orsubstituted C₃₋₇ heterocycloalkyl(C₁₋₃)alkyl, unsubstituted orsubstituted C₃₋₆ cycloalkoxy, unsubstituted or substituted C₃₋₆heterocycloalkoxy, unsubstituted or substituted C₁₋₃alkoxy(C₁₋₃)alkoxy,unsubstituted or substituted (C₃₋₆)cycloalkyl(C₁₋₃)alkoxy unsubstitutedor substituted (C₃₋₆) heterocycloalkyl(C₁₋₃)alkoxy, unsubstituted orsubstituted phenyl, unsubstituted or substituted phenyloxy,unsubstituted or substituted thienyl, unsubstituted or substitutedpyridyl, unsubstituted or substituted oxazole, unsubstituted orsubstituted thiazole, unsubstituted or substituted isoxazole,unsubstituted or substituted phenyl(C₁₋₃)alkoxy preferably benzyloxy,wherein each optional substitution in R6 is selected from fluoro,chloro, bromo, methyl, methoxy and cyano,or

R6 forms together with R7 and the carbon atoms to which R6 and R7 areattached, an unsubstituted or substituted phenyl, unsubstituted orsubstituted pyridyl, unsubstituted or substituted cyclopentyl orunsubstituted or substituted cyclohexyl, wherein each substitution, ifpresent, is selected from halogen, C₁₋₃alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl(C₁₋₃) alkyl, C₃₋₇ heterocycloalkyl(C₁₋₃)alkyl, C₁₋₃alkoxy,and C₁₋₃alkoxy(C₁₋₃)alkyl, wherein each alkyl or alkoxy can beunsubstituted or substituted with one or more substituents selected fromhalogen and C₁₋₃alkoxy,or

R6 forms together with R5 and the carbon atoms to which R6 and R5 areattached a 1,3-dioxolane, which may be unsubstituted or substituted withone or two substituents selected from fluoro and methyl,

R7 is selected from H, halogen, cyano, C₁₋₃alkyl, C₁₋₃alkoxy,C₁₋₃alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylsulfonyl, and C₁₋₃alkylsulfinyl, wherein each alkyl or alkoxy moiety can be substitutedwith one or more substituents, preferably with halogen or C₁₋₃ alkoxy,or R7 forms a ring together with R6 as described herein,

R8 is selected from hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, and halogen,wherein each alkyl or alkoxy can be unsubstituted or substituted withone or more substituents selected from halogen, cyano and methoxy, or R8forms a ring system together with R9, as described herein,

R9 is selected from hydrogen, C₁₋₃alkyl, C₁₋₃alkoxy, fluoro, chloro,bromo and iodo, wherein each alkyl or alkoxy can be unsubstituted orsubstituted with one or more substituents selected from halogen andmethoxy, or R9 forms together with R8 or R10 and the ring to which theyare attached a bicyclic ring system selected from2,1,3-benzothiadiazole, 2,1,3-benzoselenadiazole, 2,1,3-benzoxadiazole,1,3-benzothiazole, 1,3-benzoxazole which may be unsubstituted or may bepartially hydrogenated and substituted with oxo, 1,3-benzodioxole whichmay be unsubstituted or substituted with one or two substituentsselected from fluoro and methyl, 2,3-dihydrobenzothiophene, which may beunsubstituted or substituted with one or two oxo groups, and1,3-dihydro-2-benzofuran, which may be unsubstituted or substituted withone or two groups selected from oxo, fluoro and methyl, preferably withone oxo group,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyl,C₁₋₃ alkoxy, C2-C4 alkenyl, C₂₋₄ alkynyl, cyano, cyanomethyl, C₁₋₃alkylcarbonyl, C₁₋₃ alkoxycarbonyl, azido, pentafluorosulfanyl, andnitro, wherein each alkyl, alkenyl, alkynyl or alkoxy can beunsubstituted or substituted with one or more substituents selected fromhalogen and C₁₋₃alkoxy, or R10 forms a ring system together with R8, asdescribed herein,

R11 is selected from hydrogen, C₁₋₃alkyl, C₁₋₃alkoxy, fluoro, chloro,bromo, iodo, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxycarbonyl, wherein each alkyland alkoxy can be unsubstituted or substituted with one or moresubstituents selected from fluoro, chloro, bromo, iodo and C₁₋₃ alkoxy,

R12 is selected from hydrogen, C₁₋₃ alkyl, C₁₋₃alkoxy, fluoro, chloro,bromo, and iodo, wherein each alkyl and alkoxy can be unsubstituted orsubstituted with one or more substituents selected from fluoro, chloro,bromo, iodo and C₁₋₃alkoxy,

wherein if R6 is hydrogen, and X1 is N, then R5 is different fromhydrogen and is preferably iodo,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

3) A compound according to item 1,

wherein

X1 is N or C(R7),

X2 is NH,

X3 is N or C(R12),

R4 is hydrogen,

R5 is selected from hydrogen, fluoro, chloro, bromo, iodo, unsubstitutedor fluorinated C₁₋₂ alkyl, preferably methyl or trifluoromethyl,unsubstituted or fluorinated C₁₋₂ alkyloxy, unsubstituted or fluorinatedC₁₋₂ alkylcarbonyl, unsubstituted or fluorinated C₁₋₂ alkyloxycarbonyl,methylsulfinyl, and methylsulfonyl, or R5 forms a ring together with R6as described herein,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido,unsubstituted or substituted C₁₋₃alkyl, trifluoromethyl, unsubstitutedor fluorinated C₁₋₃alkylcarbonyl preferably acetyl, unsubstituted orfluorinated C₁₋₃alkoxycarbonyl, methylsulfinyl, methylsulfonyl, C₃₋₆cycloalkyl preferably cyclopropyl, C₃₋₆ cycloalkyl(C₁₋₃))alkylpreferably cyclopropylmethyl, C₃₋₆ heterocycloalkyl, C₃₋₆ cycloalkoxy,C₃₋₆ heterocycloalkoxy, unsubstituted or substituted C₁₋₃ alkoxypreferably methoxy, unsubstituted or substituted C₁₋₃alkoxy(C₁₋₃) alkoxycyclopropylmethoxy, unsubstituted or substituted phenyl, unsubstitutedor substituted phenyl(C₁₋₃)alkoxy preferably benzyloxy, unsubstituted orsubstituted phenyloxy, unsubstituted or substituted thienyl, pyridyl,oxazole, thiazole, and isoxazole, and wherein each optional substitutionin R6 is preferably selected from fluoro, chloro, methyl, methoxy, andcyano,

provided that if R6 is hydrogen, and X1 is N, then R5 is preferablydifferent from hydrogen and is preferably iodo,or

R6 forms together with R7 and the carbon atoms to which R6 and R7 areattached, an unsubstituted or substituted phenyl, an unsubstituted orsubstituted pyridyl, an unsubstituted or substituted cyclopentyl or anunsubstituted or substituted cyclohexyl, wherein each substitution, ifpresent, is selected from halogen, methyl or methoxy, wherein eachmethyl or methoxy can be unsubstituted or substituted with one or moresubstituents selected from fluoro and methoxy, or

R6 forms together with R5 and the carbon atoms to which R6 and R5 areattached, a 1,3-dioxolane which may be unsubstituted or substituted withone or two substituents selected from fluoro and methyl,

R7 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, C₁₋₃alkyl, C₁₋₃ alkyloxy, fluoro(C₁₋₃)alkyl preferably trifluoromethyl,fluoro(C₁₋₃)alkoxy preferably trifluoromethoxy, unsubstituted orfluorinated C₁₋₃ alkylcarbonyl, unsubstituted or fluorinated C₁₋₃alkoxycarbonyl, methylsulfinyl, and methylsulfonyl, or R7 forms a ringtogether with R6 as described herein,

R8 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkyloxypreferably methoxy, fluoro(C₁₋₃)alkoxy, C₁₋₃alkyl preferably methyl, andfluoro(C₁₋₃)alkyl preferably trifluoromethyl, or R8 forms a ring systemtogether with R10, as described herein,

R9 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃alkyloxypreferably methoxy, fluoro(C₁₋₃)alkoxy, C₁₋₃alkyl preferably methyl,cyano, and fluoro(C₁₋₃)alkyl preferably trifluoromethyl,

or R9 forms together with R8 and the ring to which they are attached abicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoselenadiazole, 2,1,3-benzoxadiazole, 1,3-benzoxazole whichmay be unsubstituted or may be partially hydrogenated and substitutedwith oxo (to give 2-oxo-2,3-dihydro-1,3-benzoxazole and1,3-benzodioxole, which is optionally substituted with one or twofluoros,

or R9 forms together with R10 and the ring to which they are attached abicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoselenadiazole, 2,1,3-benzoxadiazole, 1,3-benzothiazole,2,3-dihydro-1-benzothiophene, which is substituted with one or two oxo(preferably substituted with two oxo to give1,1-dioxo-2,3-dihydro-1-benzothiophene),3-oxo-1,3-dihydro-2-benzofuran-5-yl, and 1,3-benzodioxole, which isoptionally substituted with one or two fluoros,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkyl,fluoro(C₁₋₃)alkyl, preferably trifluoromethyl, C₂₋₃ alkynyl, C₁₋₃alkyloxy, fluoro(C₁₋₂)alkoxy, cyano, cyanomethyl, unsubstituted orfluorinated C₁₋₃ alkylcarbonyl preferably acetyl, unsubstituted orfluorinated C₁₋₃ alkoxycarbonyl azido, pentafluorosulfanyl, and nitro,or

R10 forms a ring system together with R9, as described herein,

R11 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkylpreferably methyl, fluoro(C₁₋₃)alkyl preferably trifluoromethyl, C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₂alkoxy, unsubstituted orfluorinated C₁₋₃ alkylcarbonyl, unsubstituted or fluorinated C₁₋₃alkoxycarbonyl and cyano,

R12 is selected from hydrogen, fluoro, chloro, bromo, iodo, C₁₋₃ alkylpreferably methyl, fluoro(C₁₋₃)alkyl preferably trifluoromethyl, C₁₋₃alkyloxy preferably methoxy, fluoro(C₁₋₂) alkoxy, and cyano.

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

4) A compound according to any one of the preceding items, wherein

X1 is N or C(R7),

X2 is NH or O,

X3 is N or C(R12),

R4 and R5 are both hydrogen,

R6 is is selected from fluoro, chloro, bromo, iodo, cyano, azido,methyl, ethyl, isopropyl, trifluoromethyl, methylsulfinyl,methylsulfonyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy,methoxyethoxy, cyclopropylmethoxy, phenyl, benzyloxy, phenyloxy,thienyl, pyridyl, oxazole, thiazole, and isoxazole,

or R6 forms together with R7 and the carbon atoms to which R6 and R7 areattached, a ring selected from phenyl, pyridyl, and cyclopentyl,

R7 is selected from hydrogen, fluoro, chloro, bromo, iodo, methoxy,difluoromethoxy, trifluoromethoxy, methyl, difluoromethyl, andtrifluoromethyl, or R7 forms a ring together with R6 as describedherein,

R8 is selected from hydrogen, fluoro, chloro, bromo, iodo, methoxy,methyl, and trifluoromethyl, or R8 forms a ring system together withR10, as described herein,

R9 is selected from hydrogen, fluoro and chloro and is preferablyhydrogen,

or R9 forms together with R8 or R10 and the ring to which they areattached a bicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoxadiazole, 2-oxo-2,3-dihydro-1,3-benzoxazole,3-oxo-1,3-dihydro-2-benzofuran-5-yl, and 1,3-benzodioxole, which isoptionally substituted with two fluoros,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl,ethynyl, propargyl, fluoro(C₁₋₂)alkyl preferably trifluoromethyl,methoxy, fluoro(C₁₋₂)alkoxy, cyano, cyanomethyl, acetyl, azido,pentafluorosulfanyl, and methoxycarbonyl, or R10 forms a ring systemtogether with R9, as described herein,

R11 is selected from hydrogen, fluoro, chloro, bromo, and methoxy,

R12 is selected from hydrogen, fluoro, chloro, or bromo.

wherein at least one of R8, R9, R10 and R11 is different from hydrogenand unsubstituted alkyl,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

5) A compound according to any one of the preceding items, wherein

X1 is N or C(R7),

X2 is NH,

X3 is N or C(R12),

R4 and R5 are both hydrogen,

R6 is selected from fluoro, chloro, bromo, azido, methyl, ethyl,isopropyl, trifluoromethyl, methylsulfonyl, cyclopropyl, methoxy,ethoxy, trifluoromethoxy, phenyl, benzyloxy, thiophen-2-yl, andthiophen-3-yl,

or R6 forms together with R7 and the carbon atoms to which R6 and R7 areattached, a ring selected from phenyl, pyridyl, and cyclopentyl,

R7 is selected from hydrogen, fluoro, chloro, and methoxy, or R7 forms aring together with R6 as described herein,

R8 is selected from hydrogen, fluoro, chloro, bromo, methoxy, andtrifluoromethyl, or R8 forms a ring system together with R10, asdescribed herein,

R9 is hydrogen or fluoro, preferably hydrogen, or R9 forms together withR8 or R10 and the ring to which they are attached a bicyclic ring systemselected from 2,1,3-benzothiadiazole, 2,1,3-benzoxadiazole,1,3-benzodioxole, or 2,2-difluoro-1,3-benzodioxole,

R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, ethynyl,propargyl, methoxy, cyano, cyanomethyl, trifluoromethyl,fluoro(C₁₋₂)alkoxy, acetyl, azido, and pentafluorosulfanyl, or R10 formsa ring system together with R9, as described herein, and wherein, in apreferred embodiment, R8 and R10 are not both hydrogen,

R11 is selected from hydrogen, fluoro, chloro, and methoxy,

R12 is selected from hydrogen, and fluoro, and pharmaceuticallyacceptable salts, solvates, isotopes and co-crystals thereof.

6) A compound according to any one of the preceding items wherein

X1 is N or C(R7),

X2 is NH,

R4 and R5 are both hydrogen,

R6 is bromo or chloro,

R7 is hydrogen, methoxy, fluoro or trifluoromethyl,

X3 is N or C(R12),

R8 is selected from hydrogen, fluoro, chloro, and methoxy,

R9 is hydrogen or fluoro,

R10 is selected from fluoro, chloro, bromo, cyano, cyanomethyl,trifluoromethyl, difluoroethoxy, trifluoroethoxy, andpentafluorosulfanyl,

R11 is selected from hydrogen, fluoro, chloro, and methoxy,

R12 is hydrogen or fluoro, wherein at least one of R8, R9, R10 and R11is different from hydrogen,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

7) A compound according to any one of the preceding items wherein

X1 is N, or C(R7),

X2 is NH,

R 4 and R5 are both hydrogen,

R6 is chloro or bromo,

R7 is hydrogen, methoxy, fluoro or trifluoromethyl,

X3 is N or C(R12),

R9 forms together with R8 and the phenyl ring to which R8 and R9 areattached a 2,1,3-benzothiadiazole or a 2,2-difluoro-1,3-benzodioxole,

R10 is hydrogen or fluoro,

R11 is selected from hydrogen, fluoro and methoxy,

R12 is hydrogen or fluoro,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

8) A compound according to any one of the preceding items

wherein

X1 is N or C(R7),

X2 is NH,

R4 and R5 are both hydrogen,

R6 is chloro or bromo, preferably chloro,

R7 is hydrogen, methoxy, fluoro or trifluoromethyl,

X3 is N or C(R12),

R8 is selected from fluoro and methoxy,

R9 is hydrogen,

R10 is selected from fluoro, chloro, bromo, iodo, cyano, cyanomethyl,difluoromethyl, trifluoromethyl, difluoroethoxy, trifluoroethoxy, andpentafluorosulfanyl,

R11 is selected from hydrogen, fluoro and methoxy,

R12 is hydrogen,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

9) A compound according to any one of the preceding items, representedby Formula II or III,

wherein R4, R5, R6, R7, if present, R8, R9, R10, R11 and X3 are asdefined in any one of the preceding items.

10) A compound according to item 9, wherein

R4 is hydrogen,

R5 is hydrogen, iodo, or methyl,

R6 is selected from hydrogen, fluoro, chloro, bromo, iodo, methyl,ethyl, isopropyl, acetyl, trifluoromethyl, methoxy, ethoxy,fluoro(C₁₋₂)alkoxy, (C₁₋₂)alkoxymethoxy, cyanomethylsulfonyl, phenyl,phenoxy, benzyloxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl,3-thienyl, cyclopropyl, cyclopropyloxy, and cyclopropylmethoxy,

R7, in Formula II, is selected from hydrogen, methyl, methoxy,trifluoromethyl, fluoro, chloro and bromo,

X3 is N or C(R12), and is preferably C(R12),

R8 is selected from hydrogen, methoxy, cyano, chloro and fluoro,

R9 is selected from hydrogen and fluoro,

R10 is selected from hydrogen, ethynyl, cyano, cyanomethyl, acetyl,fluoro, chloro, bromo, iodo, azido, nitro, trifluoromethyl,difluoroethoxy, trifluoroethoxy, and pentafluorosulfanyl,

R11 is selected from hydrogen, fluoro, chloro, and methoxy, R12 ishydrogen or fluoro,

wherein at least one of R8, R9, R10 and R11 is different from hydrogen,and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

11) A compound according to item 9,

wherein

R4 and R5 are both hydrogen,

R6 is selected from fluoro, chloro, bromo, isopropyl, benzyloxy, andtrifluoromethyl,

R7, in Formula II, is hydrogen, methoxy, fluoro, or bromo, preferablyhydrogen,

X3 is —C(R12)-,or N,

R8 is fluoro, hydrogen, or methoxy,

R9 is hydrogen,

R10 is ethynyl, trifluoromethyl, difluoroethoxy, cyano, chloro, bromo,or iodo,

R11 is selected from hydrogen and fluoro, and

R12 is selected from hydrogen and fluoro, and pharmaceuticallyacceptable salts, solvates, isotopes and co-crystals thereof.

12) A compound according to item 9.

wherein

R4, R5 are both hydrogen,

R6 is bromo, chloro, or trifluoromethyl,

R7 is hydrogen, methoxy, fluoro, or trifluoromethyl,

R8 is fluoro or methoxy,

R9 is hydrogen,

R10 is selected from fluoro, chloro, bromo, cyano, cyanomethyl,trifluoromethyl, difluoroethoxy, and pentafluorosulfanyl,

R11 is selected from hydrogen, methoxy and fluoro, and pharmaceuticallyacceptable salts, solvates, isotopes and co-crystals thereof.

13) A compound according to any one of items 1 to 5, represented by oneof the following Formulae Ila -IIc:

wherein

n is any number from 0 to 4, preferably 0, 1 or 2,

m is 0 or 1, p is any number from 0 to 3, preferably 0, 1 or 2,

any Y is an independently selected substitution from the group ofhalogen, cyano, C₁₋₆

alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkyl(C₁₋₃)alkyl, C₃₋₇ heterocycloalkyl(C₁₋₃)alkyl, C₁₋₆ alkoxy, andC₁₋₆alkoxy(C₁₋₃)alkyl wherein each alkyl or alkoxy can be unsubstitutedor substituted with one or more substituents selected from halogen andC₁₋₃ alkoxy, and

R4, R5, X3, R8, R9, R10, R11 and R12 are as described in any one ofitems 1 to 5, and pharmaceutically acceptable salts, solvates, isotopesand co-crystals thereof.

14) A compound according to item 13

wherein

m is 0, n is 0 or 1, p is 0 or 1,

any Y is selected from hydrogen, halogen, unsubstituted or fluorinatedmethyl and unsubstituted or fluorinated methoxy,

R4 and R5 are both hydrogen,

R8 is selected from hydrogen, methoxy, fluoro, and chloro, X3 is N orC(R12),

R9 is selected from hydrogen, methoxy, fluoro and chloro, and ispreferably hydrogen,

R10 is selected from hydrogen, ethynyl, cyano, cyanomethyl, fluoro,chloro, bromo, iodo, azido, trifluoromethyl, trifluoromethoxy,difluoroethoxy, trifluoroethoxy and pentafluorosulfanyl,

R11 is selected from hydrogen, fluoro, chloro, and methoxy, and

R12 is hydrogen or fluoro,

and wherein at least one of R8, R9, R10 and R11 is different fromhydrogen,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.

15) A compound according to item 13 and pharmaceutically acceptablesalts, solvates, isotopes and co-crystals thereof, wherein

m is 0, n is 0 or 1, p is 0 or 1,

any Y is selected from hydrogen, halogen, unsubstituted or fluorinatedmethyl and unsubstituted or fluorinated methoxy

X3 is C(R12)

R4 and R5 are both hydrogen,

and either

(a) R8 together with R9 and the ring to which they are attached form abicyclic ring system selected from 2,1,3-benzothiadiazole,2,1,3-benzoxadiazole, 2,1,3-benzoselanadiazole,2-oxo-2,3-dihydro-1,3-benzoxazole, unsubstituted 1,3-benzodioxole and2,2-difluoro-1,3- benzodioxole,

R10 is selected from the group of hydrogen, fluoro, chloro, bromo,trifluoromethyl, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, andcyano, and is preferably hydrogen or fluoro,

R11 is selected from hydrogen, methoxy, fluoro, chloro, bromo and cyano,and

R12 is hydrogen, fluoro, chloro, and trifluoromethyl, or

(b) R8 is hydrogen, methoxy or fluoro,

R9 together with R10 and the C atoms to which they are attached form aring selected from an 2,1 ,3-benzothiadiazole, 2,1 ,3-benzoxadiazole,and 2,2-difluoro-1 ,3-benzodioxole, ,R11 is hydrogen or fluoro, and

R12 is hydrogen or fluoro.

16) A compound according to any one of items 1 to 5, represented by oneof the following

Formulae II(d), II(e), II(f), III(a), III(b) or III(c)

wherein

R4, R5, R6, R7, R8, R10, R11 and R12 are as described in any one ofitems 1 to 5,

in Formulae II(d) and III(a) Q1 is S or 0,

in Formulae II(e) and III(b), R13 and R14 are selected from the group ofhydrogen, methyl

and fluoro and are preferably either both hydrogen or both fluoro, and

in Formulae II(f) and III(c), Q2 is S or 0, preferably S,

and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof. 17) A compound according to item 16 represented byone of the Formulae Ild, Ile, Illa and IIIb, wherein

Q1 is S or 0,

R13 and R14 are selected from hydrogen and fluoro,

R4 and R5 are both hydrogen,

R6 is selected from fluoro, chloro, bromo, trifluoromethyl, and phenyl,

R7, if present, is hydrogen, fluoro, bromo, methoxy, or trifluoromethyl,preferably hydrogen or trifluoromethyl,

R10 is selected from hydrogen and halogen, preferably from hydrogen,fluoro and chloro,

R11 is selected from hydrogen, halogen, trifluoromethyl and cyano,preferably from fluoro and hydrogen,

R12 is selected from hydrogen, halogen and trifluoromethyl.

18) A compound according to item 16, represented by one of the FormulaeIIf and IIIc,

wherein

Q2 is S or 0,

R4 and R5 are both hydrogen,

R6 is selected from fluoro, chloro, bromo, trifluoromethyl and phenyl,

R7, if present, is selected from hydrogen, methoxy, fluoro, andtrifluoromethyl,

R8 is selected from hydrogen and halogen, preferably from hydrogen andfluoro,

R11 is selected from hydrogen, halogen, trifluoromethyl and cyano, andis preferably hydrogen,

R12 is selected from hydrogen, halogen and trifluoromethyl, preferablyfrom fluoro and hydrogen, 19) A compound according to one of thepreceding items comprising at least one istope selected from ¹²³I, ¹²⁵I,¹³¹I, ¹¹C, ¹⁴C, ¹³N, ¹⁵O, ¹⁸F, ⁷⁶Br, ¹²⁴I, ²H and ³H in an enrichedamount, exceeding the natural abundance if said isotope is naturallyoccuring 20) The use of a compound according to item 19, wherein theisotope is selected from ¹²³I, ¹²⁵I, ¹³¹I, ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ⁷⁶Br and¹²⁴I and is present in an amount suitable for PET and/or SPECT imaging,in diagnosis and/or in PET or SPECT imaging.

21) A compound according to any one of the preceding items, for use intherapy.

22) A compound according to any one of the preceding items for use inthe prevention, treatment of a disorder or syndrome selected from amyelination disorder and a disorder or syndrome associated with braintissue damage.

23) A compound according to item 22, wherein the syndrome or disorder isselected from the group of multiple sclerosis (MS) including its varioussubforms, neuromyelitis optica (Devic's disease), chronic relapsinginflammatory optic neuritis, acute disseminated encephalomyelitis, acutehaemorrhagic leucoencephalitis (AHL), periventricular leukomalacia,demyelination due to viral infections, central pontine and extrapontinemyelinolysis, demyelination due to traumatic brain tissue damage,demyelination in response to hypoxia, stroke or ischaemia or othercardiovascular diseases, demyelination due to exposure to carbondioxide, cyanide, or other CNS toxins, Schilder disease, Balo concentricsclerosis, perinatal encephalopathy, neurodegenerative diseasesincluding amyotrophic lateral sclerosis (ALS). Alzheimer's disease (AD).multiple system atrophy, Parkinson's Disease, spinocerebellar ataxia(SCA) and Huntington's Disease, psychiatric disorders such asschizophrenia and bipolar disorder and peripheral myelination diseasesincluding leukodystrophies, peripheral neuropathies, Dejerine-Sottassyndrome or Charcot-Marie-Tooth disease 24) A compound according to anyone of the preceding items for use in the prevention and/or treatment ofmultiple sclerosis (MS).

25) A method for the prevention, and/or treatment of a syndrome ordisorder selected from a myelination disorder and a disorder or syndromeassociated with a brain tissue damage, which comprises administering toa patient in need thereof a therapeutically effective amount of acompound according to any one of the preceding items.

26) A method according to item 25, wherein the symptom or disorder isassociated with a myelination disorder, selected from the group ofmultiple sclerosis (MS) including its various subforms, neuromyelitisoptica (Devic's disease), chronic relapsing inflammatory optic neuritis,acute disseminated encephalomyelitis, acute haemorrhagicleucoencephalitis (AHL), periventricular leukomalacia, demyelination dueto viral infections, central pontine and extrapontine myelinolysis,demyelination due to traumatic brain tissue damage, demyelination inresponse to hypoxia, stroke or ischaemia or other cardiovasculardiseases, demyelination due to exposure to carbon dioxide, cyanide, orother CNS toxins, Schilder's disease, Balo concentric sclerosis,perinatal encephalopathy, neurodegenerative diseases includingamyotrophic lateral sclerosis (ALS). Alzheimer's disease (AD), multiplesystem atrophy, Parkinson's Disease, spinocerebellar ataxia (SCA) andHuntington Disease, psychiatric disorders such as schizophrenia andbipolar disorder and peripheral myelination diseases includingleukodystrophies, peripheral neuropathies, Dejerine-Sottas syndrome orCharcot-Marie-Tooth disease.

27) A pharmaceutical composition comprising a compound according to anyone of the preceding items, and a pharmaceutical acceptable carrier.

Experimental Part A. CHEMISTRY

The compounds of the present inventions and their syntheses routes aredescribed in more detail below.

It is to be understood that 1H-pyrrolo[2,3-b]pyridines and 1H indoles aswell as their aniline precursors typically contain a hydrogen attachedto the nitrogen atom in the 5 ring even though this hydrogen is notalways expressly indicated in the drawings herein.

A-I General Methods of Making the Compounds

The compounds of Formula I according to the invention can be preparedanalogously to conventional methods as understood by the person skilledin the art of synthetic organic chemistry.

Any reference to the synthesis of compounds of general Formula I hereinlikewise apply to the applicable compounds of the subgeneric Formula II,Ila, Ilb, IIc, Ild, Ile, Ilf, Ill, IIla, IIIb, IIIc and IV, and thespecific Example compounds disclosed herein.

According to one embodiment, some compounds of general Formula I may beprepared by reaction of a compound of Formula XI with an aniline ofFormula X according to the equation:

This reaction may be performed with chlorosulfonic acid to form thenon-isolated sulfonyl chloride intermediate XII at a temperature rangingfrom 60 to 120° C. in a polar solvent such as acetonitrile. IntermediateXII is then directly reacted with an aniline X in the presence of a basesuch as pyridine with or without a catalytic amount of4-dimethylaminopyridine (DMAP), in a polar solvent such as acetonitrileat a temperature preferably ranging from 60 to 80° C.

Alternatively, the sulfonyl chloride intermediate XII may be formedstarting from compound XI, in the presence of pyridine-sulfur trioxidecomplex in pyridine, at reflux temperature. The intermediate sulfonicacid salt may be chlorinated in the presence of a chlorinating agentsuch as triphenylphosphine/trichloroacetonitrile in a solvent such asdichloromethane at reflux temperature.

Alternatively, some compounds of general Formula I may be prepared byreaction of a sulfonyl chloride of Formula XII with an aniline ofFormula X according to the equation:

This reaction may be performed in the presence of a base such aspyridine used as solvent at room temperature.

Alternatively, some compounds of Formula I wherein X3 is N may beprepared by reaction of a sulfonamide of Formula XII-N with afluoropyridine of formula X-N.

This reaction may be performed in the presence of a base such aspotassium carbonate in a polar solvent such as dioxane at hightemperature.

Compounds of formula XII-N may be prepared by ammonolysis of sulfonylchlorides of formula XII.

This reaction may be performed with gaseous ammonia in a polar solventsuch as tetrahydrofuran at room temperature.

Alternatively, some compounds of general Formula I wherein X2=NH may beprepared by deprotection of a compound of Formula I-P wherein P is aprotecting group such as phenylsulfonyl (PhSO2) according to theequation:

This reaction may be performed in the presence of a weak base such aspotassium carbonate in a protic solvent mixture such as methanol andwater at room temperature.

Compounds of Formula I-P may be prepared by reaction of a sulfonylchloride of Formula XII-P with an aniline of Formula X. This reactionmay be performed in the presence of a base such as pyridine used assolvent at room temperature.

Compounds of Formula XII may be prepared by chlorination of a compoundof Formula IX according to the equation:

This reaction may be performed in the presence of a chlorinating agentsuch as phosphorus oxychloride or thionyl chloride in a polar solventsuch as acetonitrile at a temperature ranging from 50 to 100° c.

Compounds of Formula IX wherein may be prepared by sulfonylation of acompound of Formula XI according to the equation:

This reaction may be performed in the presence of a sulfonylating agentsuch as pyridine-sulfur trioxide complex in the presence of a base suchas pyridine used as a solvent at reflux temperature.

Alternatively, some compounds of Formula XII wherein X2=O may beprepared by chlorosulfonylation of a compound of Formula XI wherein X2=Oaccording to the equation:

This reaction may be performed in the presence of a sulfonylating agentsuch as sulfur trioxide-dimethyl formamide complex in a solvent such as1,2-dichloroethane at reflux temperature, followed by the addition of achlorinating agent such as thionyl chloride at a temperature rangingfrom 60 to 80° C.

Alternatively, some compounds of Formula XII wherein X2=S may beprepared by chlorosulfonylation of a compound of Formula XI wherein X2=Saccording to the equation:

This reaction may be performed in the presence of a sulfonylating agentsuch as chlorosulfonic acid in a solvent such as dichloromethane at roomtemperature.

Compounds of Formula XII-P wherein P is a protecting group such asphenylsulfonyl may be prepared by chlorosulfonylation of a compound ofFormula XI-P according to the equation:

This reaction may be performed in the presence of chlorosulfonic acid ina polar solvent such as acetonitrile at room temperature.

Compounds of Formula XI-P wherein P is a protecting group such asphenylsulfonyl may be prepared by protection of a compound of Formula XIaccording to the equation:

This reaction may be performed according to any method known to theperson skilled in the art.

Anilines of Formula X are commercially available or may be preparedaccording to any method known to the person skilled in the art or usingprocedures described in literature.

Alternatively, some anilines of Formula X may be prepared by reductionof a compound

VIII according to the equation:

This reaction may be performed using any reducing agent such as tindichloride in the presence of a strong acid such as concentratedhydrochloric acid or hydrogen in the presence of a catalytic amount ofpalladium on charcoal in a protic solvent such as ethanol or accordingto any method known to the person skilled in the art.

Compounds of Formula VIII are commercially available or may be preparedaccording to literature procedures or or any other methods known to theperson skilled in the art.

Compounds of Formula XI are commercially available or may be prepared bysuitable methods well known by the person skilled in the art.

Alternatively, some compounds of Formula XI wherein X1=C−R7 and whereinR7 is not an hydrogen may be prepared by reaction of a ortho-substitutednitroarene XII with a vinyl Grignard reagent XIII (Bartoli indolesynthesis) according to the equation:

This reaction may be performed using a vinyl Grignard reagent such asvinyl magnesium bromide in a polar solvent such as tetrahydrofuran atlow temperature such as −20° C.

Alternatively, some compounds having the general Formula I may beprepared by functional group conversion on already assembled analogs ofcompounds having the general Formula I using procedures described in theliterature or known to the person skilled in the art.

In particular, some compounds of Formula I wherein R6 is an aryl or anheteroaryl group may be prepared by Suzuki-type coupling starting from acompound of Formula I wherein R5 is a halogen atom, preferentiallybromine, in the presence of the corresponding boronic acid, a palladiumsalt such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium anda base such as potassium carbonate in a polar solvent such as dioxaneaccording to methods known to the person skilled in the art.

Alternatively, some compounds of Formula I wherein R6 is analkylsulfonyl group such as methylsulfonyl may be prepared starting froma compound of Formula I wherein R5 is a halogen atom, preferentiallybromine, in the presence of an alkyl sulfinate salt such as sodiummethane sulfinate and a copper salt such as copper iodide in a polarsolvent such as dimethylsulfoxide at 130° C.

Alternatively, compounds of Formula I wherein R6 is —S(O)Rx, and Rx is aC₁₋₆ alkyl may be prepared by oxidation of a compound of Formula Iwherein R6 is SRx, Rx having the same definition as above, according toany method known to the person skilled in the art. Compound of Formula Iwherein R6 is SRx may be prepared starting from a compound of Formula Iwherein R6 is a halogen atom, preferentially bromine, in the presence ofan alkyl thiolate salt, a palladium salt such astris(dibenzylideneacetone) dipalladium(0), a phosphine ligand such asxantphos in a polar solvent such as N,N-dimethylformamide undermicrowave heating at high temperature.

A-II. Abbreviations/Recurrent Reagents

Ac: acetyl

ACN: Acetonitrile

Brine: Saturated aqueous sodium chloride solution

nBu: n-butyl

tBu: tert-butyl

Cy: Cyclohexyl

dba: dibenzylideneacetone

DCM: Dichloromethane

DIPEA: N,N-diisopropylethylamine

DMAC: N,N-dimethylacetamide

DMAP: 4-dimethylaminopyridine

DMF: N,N-Dimethylformamide

DMSO: Dimethylsulfoxide

DPPA: Diphenylphosphoryl azide

dppf: 1,1′-bis(diphenylphosphino)ferrocene

ES+: Electrospray Positive Ionization

ES−: Electrospray Negative Ionization

ESI: Electrospray Ionization

EtOAc: Ethyl acetate

h: Hour

LC: Liquid Chromatography

LCMS: Liquid Chromatography Mass Spectrometry

Me: Methyl

MeOH: Methanol

min.: minutes

MOM: methoxymethyl

mw: microwave oven

NBS: N-Bromosuccinimide

NMR: Nuclear magnetic resonance

Pin: pinacolato

PMA: Phosphomolybdic acid

PMB: para-methoxybenzyl

rt: room temperature

TBAHSA: Tetrabutylammonium hydrogen sulfate

TBAF: Tetrabutylammonium fluoride

TBS: tert-butyldimethylsilyl

TEA: Triethylamine

TFA: Trifluoroacetic acid

THF: Tetrahydrofuran

TLC: Thin Layer Chromatography

Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

A-III. Analytical Methods

Commercial solvents and reagents were generally used without furtherpurification, including anhydrous solvents when appropriate (generallySure-Seal™ products from Aldrich Chemical Company or AcroSeal™ fromACROS Organics). In general reactions were followed by thin layerchromatography or Liquid Chromatography Mass Spectrometry analyses.

Mass spectrometric measurements in LCMS mode are performed usingdifferent methods and instrument as follows:

Basic LCMS Method 1:

A QDA Waters simple quadrupole mass spectrometer is used for LCMSanalysis. This spectrometer is equipped with an ESI source and an UPLCAcquity Hclass with diode array detector (200 to 400 nm). Data areacquired in a full MS scan from m/z 70 to 800 in positive mode with anbasic elution. The reverse phase separation is carried out at 45 ° C. ona Waters Acquity UPLC BEHC18 1.7 μm (2.1×50 mm) column for basicelution. Gradient elution is done with water/ACN/ammonium formate(95/5/63 mg/L) (solvent A) and ACN/water/ammonium formate (95/5/63 mg/L)(solvent B). Injection volume: 1 μL.

Full flow in MS.

Basic program “4 min” (table 1)

TABLE 1 Flow Time (min) A (%) B (%) (mL/min) 0 99 1 0.4 0.3 99 1 0.4 3.20 100 0.4 3.25 0 100 0.5 4 0 100 0.5

Basic LCMS Method 2:

Mass spectrometry (MS) spectra were recorded on an LCMS-2010EV massspectrometer (Shimadzu) with electrospray ionization (ESI) coupled to anHPLC modular Prominence (Shimadzu) using Xbridge C18-2.1×30 mm, 2.5 μm(Waters) column. A volume of 3 μL of sample solution with aconcentration of approx. 1 mg/mL was injected. The mobile phase forbasic conditions was a mixture of A) 5 mM ammonium formate +0.1% ammoniain water B) 5% mobile phase A+0.1% ammonia in acetonitrile. The gradientused was as follows-5:95(B/A) to 95:5(B/A) in 4min and hold 95:5(B/A)for next lmin.

Neutral LCMS Method 3:

Mass spectrometry (MS) spectra were recorded on an LCMS instrument(Applied Biosystems API 2000 LC/MS/MS, HPLC Agilent 1100) using thefollowing procedure: dissolving of the compounds at a concentration of1.0 mg mL-1 in ACN (Solvent A) or water (containing 2 mM ammoniumacetate) : MeOH 90:10 (Solvent B), and if necessary sonicated untilcompletely dissolved. Then, 10 pL of the solution was injected into aPhenomenex Luna C18 HPLC column (50×2.00 mm, particle size 3 pm) andelution was performed with a gradient of water : ACN (Gradient A) orwater : MeOH (Gradient B) from 90:10 to 0:100 within 10 min, startingthe gradient after 1 min, followed by elution in pure organic solventfor 10 min at a flow rate of 300 μL min-1. UV absorption was detectedfrom 220 to 400 nm using a diode array detector (DAD).

Crude materials could be purified by normal phase chromatography,(acidic or basic) reverse phase chromatography or recrystallization.

Normal phase chromatography was performed using silica gel columns(100:200 mesh silica gel or cartridges for flash chromatography systemssuch as Isolera™ Four from Biotage® or Teledyne Isco CombiFlash®).

Preparative reverse phase chromatography was performed with twodifferent instruments and according to the methods as follows:

Basic prep LCMS Method 1:

LCMS purification is using an SQD or QM Waters triple quadrupole massspectrometer for MS detection. This spectrometer is equipped with an ESIsource and a Prep LC controller

Waters quaternary pump with diode array detector (210 to 400 nm).

MS parameters: ESI capillary voltage 3 kV. Cone and Extractor voltage10. Source block temperature 120° C. Desolvation temperature 300° C.Cone gaz flow 30 L/h (Nitrogen), Desolvation Gas flow 650 L/h.Data areacquired in a full MS scan from m/z 100 to 700 in positive mode with anacidic or a basic elution.

LC parameters: The reverse phase separation is carried out at rt on anXBridge prep OBD C18 column (5 μm, 30×50 mm) (basic elution). Gradientelution is done with water (solvent A), ACN (solvent B), ammoniumbicarbonate in water 8 g/L +500 pL/L NH₄OH 30% (solvent C) (pH˜8.5).HPLC flow rate: 35 mL/min to 60 mL/min, injection volume: 1 mL. Thesplitting ratio is set at +/−1/6000 to MS (table 2).

TABLE 2 Flow Time (min) A (%) B (%) C (%) (mL/min) 0 85 5 10 35 1 85 510 35 7 5 85 10 35 9 5 95 0 60 12 5 95 0 60 12.5 85 5 10 35 16 85 5 1035

Neutral RP- HPLC Method 2:

HPLC purification of final products was performed on a Knauer Smartline1050 HPLC system using a RP-HPLC column (Knauer 20 mm i.d.,Eurospher-100 C18). The product was dissolved in methanol (20 mg per 8mL) and subjected to reversed-phase HPLC applying a gradient ofmethanol/water (70:30 to 100:0 over 24 min).

NMR spectra were recorded on different instruments:

a BRUKER AVANCEIII 400 MHz-Ultrashield NMR Spectrometer fitted with aWindows 7 Professional workstation running Topspin 3.2 software and a 5mm Double Resonance Broadband Probe (PABBI 1H/19F-BB Z-GRD Z82021/0075)or a 1 mm Triple Resonance Probe (PATXI 1H/ D-13C/15N Z-GRDZ868301/004).

a Varian 400 MHz NMR spectrometer with acquisition time (at) =2.0 sec,relaxation delay (d1)=2.0 sec and line broadening (1b)=0.5 Hz.

a Bruker Avance DRX 500 MHz NMR spectrometer

a Bruker Avance III 600 MHz NMR spectrometer

Chemical shifts are referenced to signals deriving from residual protonsof the deuterated solvents (DMSO-ds, Benzene-dsor CDCl₃). Chemicalshifts are given in parts per million (ppm) and coupling constants (J)in Hertz (Hz). Spin multiplicities are given as broad (br), singlet (s),doublet (d), triplet (t), quartet (q) and multiplet (m).

Products were generally dried under vacuum before final analyses andsubmission to biological testing

A-IV: Example Compounds and Synthesis

The names of the following compounds are IUPAC names generated by BioviaDraw Version 16.1 for Intermediates of Formula X, XI, XII and by ACDlabsversion 14.03 for Example compounds of Formula I.

Intermediates

A. Synthesis of Intermediates of Formula X A.1. Synthesis of4-fluoro-2,1,3-benzothiadiazol-7-amine X-1

Step-1: Synthesis of 4-fluoro-2,1,3-benzothiadiazole X-1 a:

To a solution of 3-fluorobenzene-1,2-diamine (1.00 g, 7.94 mmol) intoluene (20 mL) was added (sulfinylamino)benzene (10 mL) and thereaction mixture was heated to reflux for 16h. Progress of the reactionwas monitored by TLC. After completion, the reaction mixture wasconcentrated under vacuum. The crude mixture obtained was purified bycolumn chromatography (silica, 100-200 mesh, 2% EtOAc in hexanes) toafford 4-fluoro-2,1,3-benzothiadiazole X-1 a (1.06 g) as a light yellowliquid.

Yield: 87%.

¹H NMR (400 MHz, CDCl₃) δ 7.21-7.25 (m, 1H) 7.52-7.61 (m, 1H) 7.83 (d,J=8.80 Hz, 1H).

Step-2: Synthesis of 4-fluoro-7-nitro-2,1,3-benzothiadiazole X-1 b:

To H₂SO₄ (12.0 mL) was added fuming HNO₃ (8.00 mL) dropwise at 0° C. andthe reaction mixture was stirred at same temperature for 10 min. Thisnitrating mixture was added dropwise to 4-fluoro-2,1,3-benzothiadiazoleX-1 a (0.80 g, 5.19 mmol) at 0° C. The reaction mixture was stirred at0° C. for 2h. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was quenched with ice, filtered, washedwith H₂O (250 mL) and dried under vacuum to afford4-fluoro-7-nitro-2,1,3-benzothiadiazole X-1 b (0.80 g crude) as a yellowsolid.

This compound was used as such for the next reaction without furtherpurification.

¹H NMR (400 MHz, CDCl₃) δ 7.43 (t, J=8.56 Hz, 1H) 8.69 (dd, J=8.31, 3.91Hz, 1H).

Step-3: Synthesis of 4-fluoro-2,1,3-benzothiadiazol-7-amine X-1

To a solution of 4-fluoro-7-nitro-2,1,3-benzothiadiazole X-1b (0.50 g,2.51 mmol) in MeOH (50 mL) was added Zn (0.82 g, 12.5 mmol) followed byNH₄Cl (1.34 g, 25.1 mmol). The reaction mixture was heated to reflux for2h. Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was filtered through a Celite pad andthe filtrate was concentrated under vacuum. The crude obtained waspurified by column chromatography (silica, 100-200 mesh, 10% EtOAc inhexanes) to afford 0.13 g of 4-fluoro-2,1,3-benzothiadiazol-7-amine X-1as a yellow solid.

Yield: 30%.

Basic LCMS Method 2 (ES⁺): 169.85 (M+H)⁺, 97% purity.

¹H NMR (400 MHz, CDCl₃) δ 4.53 (brs, 2H) 6.52 (dd, J=8.07, 3.67 Hz, 1H)7.05-7.14 (m, 1 H).

A.2. Synthesis of 7-bromo-2,2-difluoro-1,3-benzodioxo1-4-amine X-2

To a solution of 2,2-difluoro-1,3-benzodioxol-4-amine (0.11 g, 0.66mmol) in DMF (15 mL) was added N-bromosuccinimide (0.10 g, 0.59 mmol)portionwise at 0° C. and the reaction mixture was stirred at roomtemperature for 1 h. Progress of the reaction was monitored by TLC andLCMS. After completion, the reaction mixture was quenched with cold H₂O(15 mL) and extracted with EtOAc (3×10 mL). The organic layer wasseparated, dried over anhydrous Na₂SO₄ and concentrated under vacuum.The crude obtained was purified by column chromatography (silica,100-200 mesh, 2% EtOAc in hexanes) to afford 0.1g of7-bromo-2,2-difluoro-1,3-benzodioxo1-4-amine X-2 as a brown solid.

Yield: 60%.

Basic LCMS Method 2 (ES⁻): 250.00 (M−H)⁻, 99% purity.

A.3. Synthesis of 5-fluorobenzo[c][1,2,5]thiadiazol-4-amine X-3

Step-1: Synthesis of 5-fluorobenzo[c][1,2,5]thiadiazole X-3a

To a solution of 4-fluorobenzene-1,2-diamine (1.50 g, 11.9 mmol) intoluene (20 mL) was added (sulfinylamino)benzene (0.40 mL, 35.7 mmol)and the reaction mixture was heated to reflux for 16h. Progress of thereaction was monitored by TLC and LCMS. After completion, the reactionmixture was concentrated under vacuum. The residue was diluted with H₂O(150 mL) and extracted with EtOAc (3×150 mL). The organic layer wasseparated, dried over anhydrous Na₂SO₄ and concentrated under vacuum.The crude obtained was purified by flash column chromatography (0 to 3%EtOAc in hexanes) to afford 1.36g of 5-fluoro-2,1,3-benzothiadiazoleX-3a as a light yellow liquid.

Yield: 74%.

¹H NMR (400 MHz, DMSO-d₆) δ 7.67-7.73 (m, 1H) 7.92-7.95 (m, 1H)8.15-8.19 (m, 1H).

Step-2: Synthesis of 5-fluoro-4-nitro-2,1,3-benzothiadiazole X-3b:

To a solution of 5-fluoro-2,1,3-benzothiadiazole X-3a (1.00 g, 6.49mmol) in concentrated H₂SO₄ (2 mL) was added nitrating mixture (1 mL) at−10° C. and the reaction mixture was stirred at room temperature for 3h.Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was poured in to ice-cold H₂O (50 mL)and extracted with EtOAc (3×50 mL). The organic layer was separated,dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crudeobtained was purified by flash column chromatography (0 to 8% EtOAc inhexanes) to afford 0.66g of 5-fluoro-4-nitro-2,1,3-benzothiadiazole X-3bas a brown solid.

Yield: 51%.

¹H NMR (400 MHz, DMSO-d₆) δ 7.56 (d, J=9.78 Hz, 1H) 8.20 (d, J=9.29 Hz,1H).

Step-3: Synthesis of 5-fluoro-2,1,3-benzothiadiazol-4-amine X-3

To a solution of 5-fluoro-4-nitro-2,1,3-benzothiadiazole X-3b (0.65 g,3.26 mmol) in MeOH (20 mL) was added Pd/C (0.30 g) and the reactionmixture was stirred at room temperature for 16h under hydrogen pressure.Progress of the reaction was monitored by TLC. After completion, thereaction mixture was filtered through a celite pad and the filtrate wasconcentrated under vacuum to afford 0.27g of5-fluoro-2,1,3-benzothiadiazol-4-amine X-3 as an orange solid.

Yield: 50%.

¹H NMR (400 MHz, DMSO-d₆) δ 6.09 (brs, 2H) 7.16-7.20 (m, 1H) 7.56 (t,J=10.52 Hz, 1H).

A.4. Synthesis of 7-amino-2,2-difluoro-1,3-benzodioxole-5-carbonitrileX-4

Step-1: Synthesis of 2,2-difluoro-6-nitro-1,3-benzodioxole-4-carboxylicacid X-4a:

To a solution of 2,2-difluoro-1,3-benzodioxole-4-carboxylic acid (10.0g, 49.5 mmol) in concentrated H₂SO₄ (70 mL) was added nitrating mixture(Conc.H₂SO₄: Conc.HNO₃, 6:5, 55 mL) at 0° C. and the reaction mixturewas stirred at 0° C. for 3h. Progress of the reaction was monitored byTLC and LCMS. After completion, the reaction mixture was poured intocrushed ice, filtered, washed with H₂O (200 mL) and dried in vacuum toafford 2,2-difluoro-6-nitro-1,3-benzodioxole-4-carboxylic acid X-4a(9.80 g crude) as an off-white solid used in the next step withoutfurther purification.

Basic LCMS Method 2 (ES⁻): 245.75 (M−H)⁻, 73% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (d, J=2.45 Hz, 1H) 8.62 (d, J=2.45 Hz,1H) 14.34 (brs, 1H).

Step-2: Synthesis of 6-amino-2,2-difluoro-1,3-benzodioxole-4-carboxylicacid X-4b:

To a solution of 2,2-difluoro-6-nitro-1,3-benzodioxole-4-carboxylic acidX-4a (1.00 g, 4.04 mmol) in MeOH (25 mL) was added Pd/C (0.10 g) and thereaction mixture was stirred at room temperature for 2h under hydrogenpressure. Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was filtered through a celite pad,washed with MeOH (40 mL) and the filtrate was concentrated in vacuum toafford 6-amino-2,2-difluoro-1,3-benzodioxole-4-carboxylic acid X-4b(0.76 g crude) as an off-white solid.

Basic LCMS Method 2 (ES⁻): 216.00 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 5.16 (brs, 1H) 6.48 (s, 1H) 6.70 (s, 1H)7.28 (brs, 2H).

Step-3: Synthesis of 2,2-difluoro-6-iodo-1,3-benzodioxole-4-carboxylicacid X-4c:

To a solution of 6-amino-2,2-difluoro-1,3-benzodioxole-4-carboxylic acidX-4b (0.75 g, 3.45 mmol) in 6N HCI (25 mL) was added NaNO2 (0.75 g, 10.3mmol) solution in H₂O (10 mL) at 0° C. and the reaction mixture wasstirred at same temperature for 30 min. KI (3.40 g, 20.7 mmol) solutionin H₂O (5 mL) was added dropwise at 0° C. and the reaction mixture wasstirred at same temperature for 40 min. The reaction mixture was stirredat room temperature for 16h. Progress of the reaction was monitored byTLC. After completion, the reaction mixture was extracted with EtOAc(2×25 mL). The organic layer was separated, washed with saturatedNa₂SO₂O₃ solution (2×20 mL), dried over anhydrous Na₂SO₄ andconcentrated in vacuum to afford2,2-difluoro-6-iodo-1,3-benzodioxole-4-carboxylic acid X-4c (0.41 g) asa pale yellow solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 36%.

¹H NMR (400 MHz, DMSO-d₆) δ 7.70 (d, J=1.60 Hz, 1H) 7.91 (d, J=1.60 Hz,1H).

Step-4: Synthesis of 2,2-difluoro-6-iodo-1,3-benzodioxo1-4-amine X-4d:

To a solution of 2,2-difluoro-6-iodo-1,3-benzodioxole-4-carboxylic acidX-4c (0.40 g, 1.21 mmol) in dioxane (5 mL) was added triethylamine (0.50mL, 3.65 mmol) followed by addition of diphenylphosphorylazide (0.78 mL,3.65 mmol). The reaction mixture was heated to reflux for 1 h. Progressof the reaction was monitored by TLC and LCMS. After completion, thereaction mixture was diluted with H₂O (20 mL), stirred for 30 min andextracted with EtOAc (2×25 mL). The organic layer was separated, driedover anhydrous Na₂SO₄ and concentrated under vacuum. The crude mixtureobtained was purified by column chromatography (silica, 100-200 mesh, 5%EtOAc in hexanes) to afford 0.21 g of2,2-difluoro-6-iodo-1,3-benzodioxo1-4-amine X-4d as a colorless semisolid.

Yield: 57%.

Basic LCMS Method 2 (ES⁻): 298.00 (M−H)⁻, 84% purity.

Step-5: Synthesis of7-amino-2,2-difluoro-1,3-benzodioxole-5-carbonitrile X-4:

To a solution of 2,2-difluoro-6-iodo-1,3-benzodioxo1-4-amine X-4d (5,0.20 g, 0.66 mmol) in DMF (3 mL) was added Zn (0.002 g, 0.03 mmol),Zn(CN)₂ (0.08 g, 0.73 mmol), (Ph₂P)₂ferrocene (0.04 g, 0.06 mmol) andDIPEA (0.11 mL, 0.66 mmol) and the reaction mixture was purged withargon for 10 min. Pd₂(dba)₃ (0.03 g, 0.04 mmol) was added and thereaction mixture was heated at 80° C. for 2h. Progress of the reactionwas monitored by TLC. After completion, the reaction mixture was dilutedwith EtOAc (25 mL), filtered through a celite pad and washed with H₂O(2×25 mL). The organic layer was separated, dried over anhydrous Na₂SO₄and concentrated under vacuum. The crude obtained was passed throughsilica (100-200 mesh) by using 20% EtOAc in hexanes to afford 0.07 g of7-amino-2,2-difluoro-1,3-benzodioxole-5-carbonitrile X-4 as a paleyellow solid.

Yield: 53%.

¹H NMR (400 MHz, DMSO-d₆) δ 3.72 (s, 2H) 7.80 (s, 1H) 7.87 (s, 1H).

A.5. Synthesis of 5-fluoro-2,1,3-benzothiadiazol-6-amine X-5

Step-1: Synthesis of 5-fluoro-6-nitro-2,1,3-benzothiadiazole X-5a

To a round-bottom flask were added 4-fluoro-5-nitrobenzene-1,2-diamine(0.40 g, 2.30 mmol), anhydrous DCM (10 mL) and triethylamine (TEA, 1.4mL, 1.00 mmol). The solution was stirred until the diamine wascompletely dissolved. Thionyl chloride (1 mL, 13.70 mmol) was addeddropwise at 0° C. Then the reaction mixture was heated to 40° C. for 3h. The mixture was then cooled to room temperature and concentratedunder reduced pressure. Water was added and the mixture was subsequentlyextracted with DCM (20 mLx3). The organic layers were combined and driedover MgSO₄. The solvent was evaporated and5-fluoro-6-nitro-2,1,3-benzothiadiazole X-5a was obtained as a yellowsolid (0.37 g).

Yield: 95%.

Neutral LCMS Method 3 (ES⁺): 200.0 (M+H)⁺, 89% purity

Step-2: Synthesis of 5-fluoro-2,1,3-benzothiadiazol-6-amine X-5

To a solution of 5-fluoro-6-nitro-2,1,3-benzothiadiazole X-5a (0.35 g,1.75 mmol) in a mixture of dioxane (7 mL) and ethanol (7 mL) at rt wasadded solid SnCl₂ (1.8 g, 9.50 mmol) followed by water (0.35 mL). Thereaction mixture was warmed up to 50° C. and stirred for 30 min, cooledto room temperature, concentrated and partitioned between ethyl acetateand 1N NaOH. The organic layer was washed with 1N NaOH, water, andbrine, and then dried over MgSO₄. The solvent was evaporated and theresidue was purified over silica gel eluting with petroleum ether/EtOAc(3/1) to afford 5-fluoro-2,1,3-benzothiadiazol-6-amine X-5 as a yellowpowder (0.21 g).

Yield: 68%.

Neutral LCMS Method 3 (ES⁺): 170.1 (M+H)⁺, 93% purity.

A.6. Synthesis of 4-amino-2,1,3-benzoselenodiazole X-6

Step-1: Synthesis of 2,1,3-benzoselenadiazole X-6a

A mixture of o-phenylendiamine (10.5 g, 97.1 mmol) and selenium dioxide(11.85 g, 106.8 mmol) in ethanol (100 mL) was refluxed for 10 min. Thereaction mixture was cooled to room temperature and ca. 90% of thesolvent was evaporated under reduced pressure. Subsequently,2,1,3-benzoselenadiazole X-6a was precipitated by adding water (50 mL)and filtered off under reduced pressure to afford 17.8 g of a beigesolid.

Yield: 85%.

¹H NMR: (500 MHz, DMSO-d₆) δ:7.99-7.69 (m, 2H), 7.60-7.43 (m, 2H).

Purity>95%, calculated from ¹H NMR data.

Step-2: Synthesis of 4-nitro-2,1,3-benzoselenadiazole X-6b

2,1,3-Benzoselenadiazole X-6a (6.7 g, 36.6 mmol) was dissolved inconcentrated sulfuric acid and cooled to 0° C. Subsequently, a mixtureof 65% nitric acid (3.8 mL) and concentrated sulfuric acid (7.23 mL) wasadded. The solution was stirred for 30 min at room temperature and thendiluted with an excess of ice water. The yellow precipitate(4-nitro-2,1,3-benzoselenadiazole) X-6b was filtered off and washed withwater. It was obtained in quantitative yield.

Yield: 100%. ¹H NMR (500 MHz, DMSO-d₆) δ:8.44 (d, J=7.3 Hz, 1H), 8.27(d, J=8.8 Hz, 1H), 7.77-7.68 (m, 1 H).

Purity: 80%, calculated from ¹H NMR data.

Step-3: Synthesis of 1,2,3-triaminobenzene X-6c

Tin(II) chloride dihydrate (2.22 g, 9.84 mmol) was suspended inconcentrated hydrochloric acid. To this suspension4-nitro-2,1,3-benzoselenadiazole X-6b (200 mg, 1.11 mmol) was added inportions. After the addition was completed the mixture was refluxed for5 h. Subsequently, elemental selenium was filtered off while hot. Thefiltrate was cooled to room temperature. The formed yellowish crystals(1,2,3-triaminobenzene dihydrochloride X-6c) were filtered under reducedpressure, washed with ethanol and dried to afford 1.11.g. The productwas directly used for the next step without further characterization.

Yield: 58%.

Step-4: Synthesis of 4-amino-2,1,3-benzoselenodiazole X-6

To a solution of 1 g (5.0 mmol) of 1,2,3-triaminobenzene dihydrochlorideX-6c in water (10 mL) was added a solution of SeO₂ (555 mg, 5.0 mmol) inwater (15 mL) at room temperature. After the addition was finished thereaction mixture was stirred for 15 min and then alkalized with a 30%aq. NaOH solution while cooling on an ice bath. The resulting orangeneedles were filtered off under reduced pressure, washed with water anddried. Additional purification by column chromatography (eluent: puredichloromethane) yielded 560 mg of 4-amino-2,1,3-benzoselenodiazole.

Yield: 56%.

¹H NMR (600 MHz, DMSO-d₆) δ: 7.26 (dd, J=8.9, 7.2 Hz, 1H), 6.93 (d,J=8.8 Hz, 1H), 6.35 (d, J=7.3 Hz, 1H), 5.98 (s, 2H, NH₂).

Purity>95%, calculated from ¹H NMR data.

A.7. Synthesis of 2-(4-amino-3-fluoro-phenyl)acetonitrile X-7

To a round-bottom flask, EtOH (5 mL) and3-fluoro-4-nitrophenylacetonitrile (0.05 g, 0.28 mmol) and 10% ofpalladium-charcoal (8 mg) were added at room temperature. The reactionmixture was treated with H₂ at 35 psi for 2 h and subsequently filteredthrough a Celite pad and washed with EtOH. The filtrate was concentratedin vacuum. The crude product 2-(4-amino-3-fluoro-phenyl)acetonitrile X-7was used in the next step without further purification.

Yield: 100%.

Neutral LCMS Method 3 (ES⁺): 151.10 (M+H)⁺, 98% purity.

A.8. Synthesis of 2-(4-amino-3-fluoro-phenyl)propanenitrile X-8

Step-1: Synthesis of 2-(3-fluoro-4-nitro-phenyl)propanenitrile X-8a

Into a dried flask were placed 2.35 g (24.45 mmol) of sodiumtert-butoxide, 5 mL of tert-butanol and 5 mL of DMF. The resultingsolution was cooled in an ice water bath. A solution of 1.24 g (8.85mmol) of 2-fluoronitrobenzene and 1.10 g (12.30 mmol) of2-chloropropionitrile in 3 mL of DMF was added dropwise to the coldsolution. The resulting mixture was allowed to react for 30 minutes at−10° C. and was then poured into 50 mL of 1N aq. HCI solution. Theaqueous mixture was extracted with ethyl acetate (50 mL×3), and driedover magnesium sulfate. After evaporation of the solvent the residue waspurified over silica gel eluting with petroleum ether/EtOAc (95/5) togive 2-(4-amino-3-fluorophenyl)propionitrile (0.65 g).

¹H NMR (600 MHz, DMSO-d₆) δ 8.22 (t, J=8.2 Hz, 2H), 7.69 (d, J=14.0 Hz,1 H) 7.52 (d, J=8.5 Hz, 1 H), 4.52 (q, J=7.2 Hz, 2H), 1.59 (d, J=7.3 Hz,5H).

Purity >95% calculated from iHNMR data.

Step-2: Synthesis of 2-(4-amino-3-fluoro-phenyl)propanenitrile X-8

2-(4-amino-3-fluoro-phenyl)propanenitrile X-8 was synthesized accordingto the method described for X-7.

Yield: quantitative yield %.

Neutral LCMS Method 3 (ES⁺): 165.1 (M+H)⁺, 95% purity.

A.9. Synthesis of 3-amino-6-cyanobenzo-2,1,3-thiadiazole X-9

Step-1: Synthesis of 2,3-diamino-4-nitro-benzonitrile X-9a

To a stirred solution of 2-amino-4-nitrobenzonitrile (0.1 g, 0.613 mmol)in DMSO (6 mL) at room temperature was added 1,1,1-trimethylhydraziniumiodide (0.124 g, 0.613 mmol) in one portion, followed by portionwiseaddition of potassium tert-butoxide (0.21 g, 1.84 mmol). The reactionmixture was stirred at room temperature under argon overnight. Thereaction mixture was poured into ice/water, acidified to pH 3 with 10%aq. HCI solution and extracted with DCM (20 mL×3). The combined organiclayers were dried over MgSO₄ and evaporation of the solvent and theresidue was purified over silica eluting with petroleum ether/EtOAc(2/1) to give 2,3-diamino-4-nitro-benzonitrile X-9a as a white powder(0.06 g).

Yield: 58%.

Neutral LCMS Method 3 (ES⁺): 179.1 (M+H)⁺, 98% purity.

Step-2 and 3: 4-amino-2,1,3-benzothiadiazole-7-carbonitrile X-94-amino-2,1,3-benzothiadiazole-7-carbonitrile X-9 was synthesizedaccording to the method described for X-5.

Yield: 42%.

Neutral LCMS Method 3 (ES⁺): 176.9 (M+H)⁺, 98% purity.

A.10. Synthesis of 2,1,3-benzoselenadiazol-5-amine X-10

To a solution of SnCl2 (5.6 g, 30 mmol) in 10 mL of concentrated HCI wasadded 4-nitro-ortho-phenylenediamine (1.0 g, 6.53 mmol) at 50° C. Themixture was stirred at 50° C. for 0.5 h and cooled to room temperature.Subsequently, a solution of SeO₂ (0.73 g, 6.53 mmol) in water was addedunder vigorous stirring. The resulting orange suspension was neutralizedwith a conc. NaHCO₃ solution (ca. 250 mL) and extracted with DCM (5times, 100 mL each). The combined organic extracts were dried overMgSO₄, filtered and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel 60 (eluent: DCM :MeOH=9.5 : 0.5) and subsequent crystallization from diethyl etheryielding 912 mg of 2,1,3-benzoselenadiazol-5-amine X-10 as orangeneedles.

Yield: 71%

¹H NMR (500 MHz, DMSO-d₆) δ: 7.51 (d, J=9.4 Hz, 1H), 7.12 (dd, J=9.5,2.2 Hz, 1H), 6.52 (d, J=2.2 Hz, 1H), 6.01 (s, 2H, NH₂).

A.11. Synthesis of 2-(6-amino-5-methoxy-3-pyridyl)acetonitrile X-11:

To a solution of 5-bromo-3-methoxy-pyridin-2-amine (0.20 g, 0.98 mmol)and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.23 g,1.18 mmol) in DMSO (4.8 mL) was added KF (0.17 g, 2.96 mmol) solution inH₂O (2.9 mL). The reaction mixture was purged with argon for 15 minfollowed by addition of PdCl₂(dppf) (0.14 g, 0.19 mmol). The reactionmixture was heated at 120° C. for 16h. Progress of the reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasfiltered through a Celite pad and filtrate was diluted with an aqueousNaCI (20 mL) solution. The aqueous layer was extracted with EtOAc (2×60mL). The organic layer was separated, dried over anhydrous Na ₂SO₄ andconcentrated under vacuum to afford2-(6-amino-5-methoxy-3-pyridyl)acetonitrile X-11 (0.15 g) as a brownsolid.

Yield: 94%

Basic LC-MS Method 2 (ES⁻): 164 (M−H)⁻, 58% purity.

A.12. Synthesis of 4-chloro-5-(difluoromethoxy)-2-fluoro-aniline X-12:

Step-1: Synthesis of1-chloro-2-(difluoromethoxy)-5-fluoro-4-nitro-benzene X-12a:

To a solution of 2-chloro-4-fluoro-5-nitro-phenol (0.50 g, 2.61 mmol) inCH₃CN (10 mL) was added KOH (0.73 g, 13.0 mmol) at 0° C. and thereaction mixture was stirred at same temperature for 30 min.1-[[bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane (3.48 g, 13.0mmol) was added dropwise at 0° C. and the reaction mixture was stirredat room temperature for 3h. Progress of the reaction was monitored byTLC and LCMS. After completion, the reaction mixture was diluted withH₂O (20 mL) and extracted with EtOAc (20 mL). The organic layer wasseparated, dried over anhydrous Na₂SO₄ and concentrated under vacuum.The crude obtained was purified by column chromatography (silica,100-200 mesh, 0 to 6% EtOAc in hexanes) to afford1-chloro-2-(difluoromethoxy)-5-fluoro-4-nitro-benzene X-12a (0.46 g) asa colourless oil.

Yield: 73%

¹H NMR (400 MHz, DMSO-d₆) δ 7.41 (t, J=72 Hz, 1H) 8.15 (d, J=6.80 Hz,1H) 8.21 (d, J=6.80 Hz, 1H).

Step-2: Synthesis of 4-chloro-5-(difluoromethoxy)-2-fluoro-aniline X-12:

To a solution of 1-chloro-2-(difluoromethoxy)-5-fluoro-4-nitro-benzeneX-12a (0.15 g, 0.59 mmol) in MeOH (7 mL) was added Pd/C (0.026 g, 0.24mmol) and the reaction mixture was stirred at room temperature for 30min under hydrogen pressure. Progress of the reaction was monitored byTLC and LCMS. After completion, the reaction mixture was filteredthrough celite celiteand washed with MeOH (10 mL). The filtrate wasconcentrated under vacuum to afford4-chloro-5-(difluoromethoxy)-2-fluoro-aniline X-12 (0.13 g) as a brownsemi solid. This compound was used as such for the next reaction withoutfurther purification.

Yield: 80%

Basic LC-MS Method 2 (ES⁻): 210 (M−H)⁻, 78% purity.

A.13. Synthesis of 4-fluoro-2,1,3-benzoxadiazol-7-amine X-13:

Step-1: Synthesis of 4-fluoro-7-nitro-2,1,3-benzoxadiazole X-13a:

To a solution of 4-fluoro-2,1,3-benzoxadiazole (1.00 g, 7.24 mmol) inConc.H2SO4 (8 mL) was added nitrating mixture (H2504: HNO3, 3:1, 2.40mL) dropwise at -10° C. The reaction mixture was stirred at the sametemperature for 1 h. Progress of the reaction was monitored by TLC andLCMS. After completion, the reaction mixture was quenched with H₂O (250mL) and extracted with EtOAc (2×250 mL). The organic layer wasseparated, dried over anhydrous Na₂SO₄ and concentrated under vacuum.The crude obtained was purified by flash column chromatography (0 to 10%EtOAc in hexanes) to afford 4-fluoro-7-nitro-2,1,3-benzoxadiazole X-13a(0.39 g) as a yellow solid.

Yield: 30%

¹H NMR (400 MHz, DMSO-d₆) δ 7.70 (d, J=8.40 Hz, 1H) 8.77-8.80 (m, 1 H).Step-2: Synthesis of 4-fluoro-2,1,3-benzoxadiazol-7-amine X-13:

To a solution of 4-fluoro-7-nitro-2,1,3-benzoxadiazole X-13a (0.13 g,0.71 mmol) in MeOH (12 mL) was added Pd/C (0.04 g) at 0° C. and thereaction mixture was stirred at room temperature for 1 h under hydrogenpressure. Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was filtered through a Celite bed,washed with MeOH (3 x 10 mL). The filtrate was concentrated under vacuumto afford 4-fluoro-2,1,3-benzoxadiazol-7-amine X-13 (0.12 g crude) as abrown semi solid.

This compound was used as such for the next reaction without furtherpurification.

Basic LC-MS Method 2 (ES⁻): 152 (M−H)⁻, 80% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.18 (d, J=8.00 Hz, 1H), 6.40 (brs, 2H),7.14-7.20 (m, 1H).

A.14. Synthesis of 5-chloro-3,6-difluoro-pyridin-2-amine X-14:

To a solution of 3-chloro-2,5,6-trifluoro-pyridine (0.50 g, 2.98 mmol)in DMSO (10 mL) was added 25% aqueous NH3 (4 mL) and the reactionmixture was heated in steel bumb at 100° C. for 12h. Progress of thereaction was monitored by TLC and LCMS. After completion, the reactionmixture was diluted with H₂O (200 mL) and extracted with EtOAc (400 mL).The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum to afford5-chloro-3,6-difluoro-pyridin-2-amine X-14 (0.41 g crude) as a yellowsolid.

This compound was used as such for the next reaction without furtherpurification.

¹H NMR (400 MHz, DMSO-d₆) δ 6.85 (s, 2H), 7.80-7.85 (m, 1H).

A.15. Synthesis of 3,6-difluoropyridin-2-amine X-15:

To a solution of 5-chloro-3,6-difluoro-pyridin-2-amine X-14 (0.50 g,3.03 mmol) in MeOH (100 mL) was added triethylamine (5 mL) and Pd/C(0.40 g) and the reaction mixture was stirred at room temperature underhydrogen pressure in parr shaker for 10h. Progress of the reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasfiltered through celite, and filtrate was concentrated under vacuum. Theresidue was diluted with H₂O (200 mL) and extracted with 10% MeOH in DCM(200 mL). The organic layer was separated, dried over anhydrous Na₂SO₄and concentrated under vacuum to afford 3,6-difluoropyridin-2-amine X-15(0.21 g crude) as an off-white solid.

This compound was used as such for the next reaction without furtherpurification.

Basic LC-MS Method 2 (ES⁺): 130 (M)⁺, 91% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.09-6.11 (m, 1H) 6.57 (brs, 2H) 7.44-7.50(m, 1H).

A.16. Synthesis of 5-bromo-3,6-difluoro-pyridin-2-amine X-16:

To a solution of 3,6-difluoropyridin-2-amine X-15 (0.60 g, 4.19 mmol) inCH₃CN (40 mL) was added NBS (0.52 g, 2.93 mmol) and the reaction mixturewas stirred in absence of light at room temperature for 30 min. NBS(0.52 g, 2.93 mmol) solution in CH₃CN (10 mL) was added and the reactionmixture was stirred at room temperature for 30 min. Progress of thereaction was monitored by TLC and LCMS. After completion, the reactionmixture was diluted with H₂O (100 mL) and extracted with EtOAc (160 mL).The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude obtained was purified by columnchromatography (silica, 100-200 mesh, 5 to 10% EtOAc in hexanes) toafford 5-bromo-3,6-difluoropyridin-2-amine X-16 (0.70 g) as an off-whitesolid.

Yield: 79%

Basic LC-MS Method 2 (ES⁻): 207 (M−H)⁻, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.86 (brs, 2H) 7.82-7.91 (m, 1H). A.17.Synthesis of 6-amino-5-fluoro-3H-isobenzofuran-1-one X-17:

Step-1: Synthesis of 5-fluoro-6-nitro-3H-isobenzofuran-1-one X-17a:

To a solution of 5-fluoro-3H-isobenzofuran-1-one (0.10 g, 0.65 mmol) inconcentrated H₂50₄ (1 mL) was added KNO3 (0.13 g, 1.31 mmol) at 0° C.The reaction mixture was stirred at room temperature for 2h. Progress ofthe reaction was monitored by TLC and LCMS. After completion, thereaction mixture was quenched with ice and extracted with EtOAc (3×30mL). The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude obtained was purified bycombi-flash column chromatography (15 to 20% EtOAc in hexanes) to afford5-fluoro-6-nitro-3H-isobenzofuran-1-one X-17a (0.063 g) as an off-whitesolid.

Yield: 48%

Basic LC-MS Method 2 (ES⁻): 196 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 5.51 (s, 2H) 7.95 (d, J=10.27 Hz, 1H) 8.54(d, J=6.85 Hz, 1H).

Step-2: Synthesis of 6-amino-5-fluoro-3H-isobenzofuran-1-one X-17:

To a solution of 5-fluoro-6-nitro-3H-isobenzofuran-1-one X-17a (0.06 g,0.30 mmol) in MeOH (10 mL) was added Pd/C (0.015 g, 0.02 mmol) and thereaction mixture was stirred at room temperature for 2h under hydrogenpressure. Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was filtered through celite, washedwith MeOH (3×10 mL). The filtrate was concentrated under vacuum to6-amino-5-fluoro-3H-isobenzofuran-1-one X-17 (0.054 g crude) as anoff-white solid.

This compound was used as such for the next reaction without furtherpurification. Basic LC-MS Method 2 (ES⁻): 166 (M−H)⁻, 95% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 5.20 (s, 2H) 5.59 (s, 2H) 7.12 (d, J=7.83Hz, 1H) 7.32 (d, J=10.76 Hz, 1H).

A.18. Synthesis of 4-(2,2-difluoroethoxy)-2,5-difluoro-aniline X-18:

Step-1: Synthesis of 1-(2,2-difluoroethoxy)-2,5-difluoro-4-nitro-benzeneX-18a:

To a solution of 2,5-difluoro-4-nitro-phenol (0.30 g, 1.71 mmol) and2,2-difluoroethanol (0.28 g, 3.43 mmol) in toluene (4 mL) was added(cyanomethylene)tributylphosphorane (0.49 g, 2.06 mmol) and the reactionmixture was heated in a sealed tube at 100° C. for 6h. Progress of thereaction was monitored by TLC and LCMS. After completion, the reactionmixture was diluted with H₂O (30 mL) and extracted with EtOAc (2×30 mL).The organic layer was separated, washed with brine (20 mL), dried overanhydrous Na₂SO₄ and concentrated under vacuum. The crude obtained waspurified by column chromatography (silica, 100-200 mesh, 10% EtOAc inhexanes) to afford 1-(2,2-difluoroethoxy)-2,5-difluoro-4-nitro-benzeneX-18a (0.20 g) as a pale brown liquid.

Yield: 39%

¹H NMR (400 MHz, DMSO-d₆) δ 4.54-4.68 (m, 2H) 6.48 (t, J=54 Hz, 1H) 7.65(m, 1H) 8.19-8.28 (m, 1H).

Step-2: Synthesis of 4-(2,2-difluoroethoxy)-2,5-difluoro-aniline X-18:

To a solution of 1-(2,2-difluoroethoxy)-2,5-difluoro-4-nitro-benzeneX-18a (0.20 g, 0.67 mmol) in MeOH (6 mL) was added Pd/C (0.014 g, 0.13mmol) and the reaction mixture was stirred at room temperature for 3hunder hydrogen pressure. Progress of the reaction was monitored by TLCand LCMS. After completion, the reaction mixture was filtered throughcelite, washed with MeOH (2×20 mL) and filtrate was concentrated undervacuum to afford 4-(2,2-difluoroethoxy)-2,5-difluoro-aniline X-18 (0.16g) as a pale yellow liquid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 78%

Basic LC-MS Method 2 (ES⁺): 210 (M+H)⁺, 68% purity. A.19. Synthesis of3,6-difluoro-5-[(E)-3-methoxyprop-1-enyl]pyridin-2-amine X-19:

To a solution of 5-bromo-3,6-difluoropyridin-2-amine X-16 (1.00 g, 4.68mmol) in toluene (26 mL) and H₂O (4 mL) was addedTRANS-3-METHOXY-1-PROPENYLBORONIC ACID PINACOL ESTER (1.39 g, 7.02 mmol)and K₂CO₃ (1.94 g, 14.0 mmol). The reaction mixture was purged withargon for 20 min followed by addition of PdCl₂(dppf) (0.34 g, 0.47mmol). The reaction mixture was heated at 120° C. for 16h. Progress ofthe reaction was monitored by TLC and LCMS. After completion, thereaction mixture was diluted with H₂O (250 mL) and extracted with EtOAc(500 mL). The organic layer was separated, dried over anhydrous Na₂SO₄and concentrated under vacuum. The crude obtained was purified by columnchromatography (silica, 100-200 mesh, 40% EtOAc in hexanes) to afford3,6-difluoro-5-[(E)-3-methoxyprop-1-enyl]pyridin-2-amine X-19 (0.803 g)as an off-white solid.

Yield: 82%

Basic LC-MS Method 2 (ES⁺): 201 (M+H)⁺, 95% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.24 (s, 3H) 3.98 (dd, J=5.62, 1.22 Hz, 2H)6.14-6.21 (m, 1H) 6.41 (dd, J=16.14, 0.98 Hz, 1H) 6.74 (s, 2H) 7.76-7.82(m, 1H).

A.20. Synthesis of 3,6-difluoro-5-(3-methoxypropyl)pyridin-2-amine X-20:

To a solution of3,6-difluoro-5-[(E)-3-methoxyprop-1-enyl]pyridin-2-amine X-19 (0.39 g,1.87 mmol) in MeOH (15 mL) was added Pd/C (0.10 g, 0.94 mmol) and thereaction mixture was stirred at room temperature for 6h under hydrogenpressure. Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was filtered through celite, washedwith MeOH (20 mL) and filtrate was concentrated under vacuum to afford3,6-difluoro-5-(3-methoxypropyl)pyridin-2-amine X-20 (0.368 g) as yellowliquid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 89%

Basic LC-MS Method 2 (ES⁺): 203 (M+H)⁺, 91% purity.

A.21. Synthesis of 5-chloro-3-fluoro-6-methoxy-pyridin-2-amine X-21:

To a solution of 5-chloro-3,6-difluoro-pyridin-2-amine X-14 (0.50 g,2.97 mmol) in MeOH (25 mL) was added NaOMe (0.48 g, 8.92 mmol) and thereaction mixture was heated at 100° C. for 24h. Progress of the reactionwas monitored by TLC and LCMS. After completion, the reaction mixturewas concentrated under vacuum. The residue was diluted with H₂O (100 mL)and extracted with DCM (200 mL). The organic layer was separated, driedover anhydrous Na₂SO₄ and concentrated under vacuum to afford5-chloro-3-fluoro-6-methoxy-pyridin-2-amine X-21 (0.40 g) as anoff-white solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 72%

¹H NMR (400 MHz, DMSO-d₆) δ 3.80 (s, 3H) 6.35 (s, 2H) 7.58 (d, J=9.78Hz, 1 H).

A.22. Synthesis of 2-(6-amino-5-fluoro-2-methoxy-3-pyridyl)acetonitrileX-22:

Step-1: Synthesis of 5-bromo-3-fluoro-6-methoxypyridin-2-amine X-22a:

To a solution of 5-bromo-3,6-difluoropyridin-2-amine X-16 (0.50 g, 2.34mmol) in MeOH (25 mL) was added NaOMe (0.38 g, 7.02 mmol) and thereaction mixture was heated at 100° C. for 18h. Progress of the reactionwas monitored by TLC and LCMS. After completion, the reaction mixturewas concentrated under vacuum. The residue was diluted with H₂O (100 mL)and extracted with DCM (200 mL). The organic layer was separated, driedover anhydrous Na₂SO₄ and concentrated under vacuum. The crude obtainedwas purified by column chromatography (silica, 100-200 mesh, 5 to 10%EtOAc in hexanes) to afford 5-bromo-3-fluoro-6-methoxypyridin-2-amineX-22a (0.403 g) as an off-white solid.

Yield: 71%

Basic LC-MS Method 2 (ES⁺): 221 (M-FH)+, 91% purity.

1H NMR (400 MHz, DMSO-d₆) δ 3.79 (s, 3H) 6.39 (s, 2H) 7.63-7.69 (m, 1H).

Step-2: Synthesis of2-(6-amino-5-fluoro-2-methoxy-3-pyridyl)acetonitrile X-22:

To a solution of 5-bromo-3-fluoro-6-methoxypyridin-2-amine X-22a (0.37g, 1.52 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ypisoxazole (0.39 g, 1.97mmol) in DMSO (8 mL) and H₂O (4.54 mL) was added KF (0.27 g, 4.56 mmol)and the reaction mixture was purged with argon for 20 min. PdCl₂(dppf)(0.22 g, 0.30 mmol) was added and the reaction mixture was heated at110° C. for 16h. Progress of the reaction was monitored by TLC and LCMS.After completion, the reaction mixture was diluted with H₂O (100 mL) andextracted with EtOAc (200 mL). The organic layer was separated, driedover anhydrous Na₂SO₄ and concentrated under vacuum. The crude obtainedwas purified by column chromatography (silica, 100-200 mesh, 40% EtOAcin hexanes) to afford2-(6-amino-5-fluoro-2-methoxy-3-pyridyl)acetonitrile X-22 (0.135 g) as apale yellow solid.

Yield: 48%

Basic LC-MS Method 2 (ES⁺): 182 (M+H)⁺, 97% purity. 1H NMR (400 MHz,DMSO-d₆) δ 3.61 (s, 2H) 3.79 (s, 3H) 6.22 (s, 2H) 7.36 (d, J=10.34 Hz,1H).

A.23. Synthesis of 2-(4-amino-2,5-difluorophenoxy)acetonitrile X-23

Step-1: Synthesis of 2-(2,5-difluoro-4-nitro-phenoxy)acetonitrile X-23a

To a solution of 2,5-difluoro-4-nitro-phenol (0.60 g, 3.43 mmol) in DMF(6 mL) was added K₂CO₃ (0.95 g, 6.85 mmol). The reaction mixture wascooled at 0 to 5° C. followed by slowly addition of bromoacetonitrile(0.29 mL, 4.11 mmol). The reaction mixture was stirred at roomtemperature for 16h. Progress of the reaction was monitored by TLC andLCMS. After completion, the reaction mixture was poured in to ice-coldH₂O (35 mL) and extracted with EtOAc (2 x 50 mL). The organic layer wasseparated, dried over anhydrous Na₂SO₄ and concentrated under vacuum toafford 2-(2,5-difluoro-4-nitro-phenoxy)acetonitrile X-23a (0.51 g) as abrown solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 70%

¹H NMR (400 MHz, DMSO-d₆) δ 5.93 (s, 2 H) 7.66- 7.70 (m, 1 H) 8.23-8.27(m, 1 H)

Step-2: Synthesis of 2-(4-amino-2,5-difluorophenoxy)acetonitrile X-23:

To a suspension of NH4C1 (0.63 g, 11.7 mmol) and Fe (0.39 g, 7.01 mmol)in H₂O (15 mL) was added solution of2-(2,5-difluoro-4-nitro-phenoxy)acetonitrile X-23a (0.50 g, 2.34 mmol)in MeOH (28 mL). The reaction mixture was heated at 50° C. for 2h.Progress of the reaction was monitored by TLC. After completion, thereaction mixture was filtered, washed with MeOH (20 mL) and filtrate wasconcentrated under vacuum. The residue was extracted with EtOAc (2×25mL). The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude obtained was purified by columnchromatography (silica, 100-200 mesh, 30% EtOAc in hexanes) to afford2-(4-amino-2,5-difluorophenoxy)acetonitrile X-23 (0.17 g) as pale yellowsolid.

Yield: 40%

¹H NMR (400 MHz, DMSO-d₆) δ 5.04 (s, 2 H) 5.22 (s, 2 H) 6.62-6.67 (m, 1H) 7.12-7.17 (m, 1 H)

A.24. Synthesis of 4-(cyclopropylmethoxy)-2,5-difluoroaniline X-24

Step-1: Synthesis of 1-(cyclopropylmethoxy)-2,5-difluoro-4-nitrobenzeneX-24a

To a solution of 2,5-difluoro-4-nitro-phenol (0.50 g, 2.86 mmol) in DMF(3 mL) was added K₂CO₃ (1.97 g, 14.3 mmol) and the reaction mixture wasstirred at room temperature for 20 min. Cyclopropylmethyl bromide (0.77g, 5.71 mmol) was added at 0° C. and the reaction mixture was heated at60° C. for 24h. Progress of the reaction was monitored by TLC and LCMS.After completion, the reaction mixture was diluted with H₂O (60 mL) andextracted with EtOAc (3×30 mL). The organic layer was separated, washedwith brine (2×30 mL), dried over anhydrous Na₂SO₄ and concentrated undervacuum to afford 1-(cyclopropylmethoxy)-2,5-difluoro-4-nitrobenzeneX-24a (0.584 g) as a yellow liquid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 89%

¹H NMR (400 MHz, DMSO-d₆) δ 0.32-0.41 (m, 2H) 0.59-0.66 (m, 2H)1.22-1.34 (m, 1H) 4.07 (d, J=7.34 Hz, 2H) 7.46 (dd, J=13.21, 6.85 Hz,1H) 8.16 (dd, J=11.00, 7.58 Hz, 1H).

Step-2: Synthesis of 4-(cyclopropylmethoxy)-2,5-difluoroaniline X-24

To a solution of 1-(cyclopropylmethoxy)-2,5-difluoro-4-nitrobenzeneX-24a (0.20 g, 0.87 mmol) in MeOH (10 mL) was added Pd/C (0.05 g, 0.09mmol) and the reaction mixture was stirred at room temperature for 3hunder hydrogen pressure. Progress of the reaction was monitored by TLCand LCMS. After completion, the reaction mixture was filtered throughcelite, washed with MeOH (3×15 mL) and filtrate was concentrated undervacuum. The crude obtained was purified by combi-flash columnchromatography (5 to 10% EtOAc in hexanes) to afford4-(cyclopropylmethoxy)-2,5-difluoroaniline X-24 (0.127 g) as a brownsolid.

Yield: 62%

Basic LC-MS Method 2 (ES⁺):

200 (M+H)⁺, 84% purity.

A.25. Synthesis of 3,5-dimethoxypyridin-2-amine X-25

To a solution of 5-bromo-3-methoxy-pyridin-2-amine (0.50 g, 2.46 mmol),1,10-phenanthroline (0.13 g, 0.74 mmol) and CuBr (0.21 g, 1.48 mmol) inMeOH (25 mL) was added Cs₂CO₃ (1.61 g, 4.93 mmol). The reaction mixturewas heated at 120° C. for 24h. Progress of the reaction was monitored byTLC and LCMS. After completion, the reaction mixture was concentratedunder vacuum. The residue was diluted with H₂O (50 mL) and extractedwith EtOAc (2×40 mL). The organic layer was separated, dried overanhydrous Na₂SO₄ and concentrated under vacuum. The crude obtained waspurified by column chromatography (silica, 100-200 mesh, 1 to 5% MeOH inDCM) to afford 3,5-dimethoxypyridin-2-amine X-25 (0.27 g) as a palebrown liquid.

Yield: 57%

Basic LC-MS Method 2 (ES⁺): 155 (M+H)⁺, 80% purity.

A.26. Synthesis of 6-amino-5-fluoro-isoindolin-1-one X-26

Step-1: Synthesis of 5-fluoro-6-nitroisoindolin-1-one X-26a

To a solution of 5-fluoroisoindolin-1-one (1.00 g, 6.62 mmol) in H₂50₄(15 mL) was added KNO₃ (1.00 g, 9.92 mmol) at 0° C. and the reactionmixture was stirred at same temperature for 1 h. Progress of thereaction was monitored by TLC and LCMS. After completion, the reactionmixture was diluted with cold H₂O (250 mL) and extracted with EtOAc (250mL). The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude obtained was purified by washingwith DCM (4 mL) and pentane (10 mL) and dried under vacuum to afford5-fluoro-6-nitroisoindolin-1-one X-26a (0.60 g) as an off-white solid.

Yield: 46%

Basic LC-MS Method 2 (ES⁻): 195 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 4.51 (s, 2H) 7.86 (d, J=10.88 Hz, 1H) 8.29(d, J=6.85 Hz, 1H) 8.95 (brs, 1H).

Step-2: Synthesis of 6-amino-5-fluoro-isoindolin-1-one X-26

To a solution of 5-fluoro-6-nitroisoindolin-1-one X-26a (0.20 g, 1.02mmol) in MeOH (10 mL) was added Pd/C (0.05 g, 0.47 mmol) and thereaction mixture was stirred at room temperature for 2h under hydrogenpressure. Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was filtered through celite, washedwith MeOH (10 mL) and filtrate was concentrated under vacuum to afford6-amino-5-fluoro-isoindolin-1-one X-26 (0.155 g) as an off-white solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 89%

Basic LCMS Method 2 (ES⁺): 167 (M+H)⁺, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 4.17 (s, 2H) 5.32 (s, 2H) 7.02 (d, J=8.31Hz, 1H) 7.19 (d, J=10.76 Hz, 1H) 8.33 (brs, 1H).

A.27. Synthesis of 6-amino-5-fluoro-3-methyl-3H-isobenzofuran-1-one X-27

Step-1: Synthesis of 5-fluoro-3-methyl-3H-isobenzofuran-1-one X-27a

To a solution of 5-fluoro-3H-isobenzofuran-1-one (1.00 g, 6.57 mmol) inDMF (5 mL) was added CH₃1 (0.82 mL, 13.1 mmol) at -20° C. followed byaddition of NaH (0.34 g, 7.89 mmol) portion wise. The reaction mixturewas stirred at room temperature for 3h. Progress of the reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasdiluted with ice-cold saturated aqueous NH4C1 solution (50 mL) andextracted with EtOAc (2×30 mL). The organic layer was separated, driedover anhydrous Na₂SO₄ and concentrated under vacuum. The crude obtainedwas purified by combi-flash column chromatography (4% EtOAc in hexanes)to afford 5-fluoro-3-methyl-3H-isobenzofuran-1-one X-27a (0.44 g) an asan off-white solid.

Yield: 35%

Basic LCMS Method 2 (ES⁺): 167 (M+H)⁺, 87% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 1.56 (d, J=6.36 Hz, 3H) 5.68 (q, J=6.36 Hz,1H) 7.41-7.48 (m, 1 H) 7.62 (dd, J=8.80, 1.96 Hz, 1H) 7.87-7.93 (m, 1H).

Step-2: Synthesis of 5-fluoro-6-nitro-3-methyl-3H-isobenzofuran-1-oneX-27b

To a solution of 5-fluoro-3-methyl-3H-isobenzofuran-1-one X-27a (0.40 g,2.10 mmol) in Conc. H₂SO₄ (4 mL) was added KNO₃ (0.26 g, 2.52 mmol) at0° C. and the reaction mixture was stirred at room temperature for 2h.Progress of the reaction was monitored by TLC.

After completion, the reaction mixture was diluted with ice-cold H₂O (25mL) and extracted with EtOAc (2×20 mL). The organic layer was separated,washed with cold saturated NaHCO₃ (25 mL) solution, dried over anhydrousNa₂SO₄ and concentrated under vacuum. The crude obtained was purified bycombi-flash column chromatography (12 to 15% EtOAc in hexanes) to afford5-fluoro-6-nitro-3-methyl-3H-isobenzofuran-1-one X-27b (0.145 g, 33%) asan off-white solid.

Yield: 33%

¹H NMR (400 MHz, DMSO-d₆) δ 1.61 (d, J=6.85 Hz, 3H) 5.82 (q, J=6.85 Hz,1H) 8.03-8.07 (m, 1 H) 8.53 (d, J=6.85 Hz, 1H).

Step-3: Synthesis of 6-amino-5-fluoro-3-methyl-3H-isobenzofuran-1-oneX-27

To a solution of 5-fluoro-6-nitro-3-methyl-3H-isobenzofuran-1-one X-27b(0.14 g, 0.66 mmol) in MeOH (5 mL) was added Pd/C (0.02 g) and thereaction mixture was stirred at room temperature for 2h under hydrogenpressure. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was filtered through celite, washedwith EtOAc (2×10 mL) and filtrate was concentrated under vacuum toafford 6-amino-5-fluoro-3-methyl-3H-isobenzofuran-1-one X-27 (0.11 g,92%) as an off-white solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 92%

¹H NMR (400 MHz, DMSO-d₆) δ 1.48 (d, J=6.85 Hz, 3H) 5.49 (q, J=6.52 Hz,1 H) 5.60 (s, 2H) 7.09 (d, J=7.82 Hz, 1 H) 7.36 (d, J=10.27 Hz, 1 H).

A.28. Synthesis of 3-methoxy-5-(trifluoromethyl)pyridin-2-amine X-28

Step-1: Synthesis of 2-chloro-3-methoxy-5-(trifluoromethyl)pyridineX-28a

To a solution of 2-chloro-5-(trifluoromethyl)pyridin-3-ol (0.75 g, 3.80mmol) in DMF (15 mL) was added NaH (0.26 g, 6.45 mmol) slowly at 0° C.and the reaction mixture was stirred at same temperature for 15 min.CH₃1 (0.40 mL, 6.45 mmol) was added at 0° C. and the reaction mixturewas stirred at same temperature for 15 min. The reaction mixture wasstirred at room temperature for 30 min. Progress of the reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasquenched with ice-cold H₂O (100 mL) and extracted with EtOAc (250 mL).The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude obtained was purified by flashcolumn chromatography (silica, 230-400 mesh, 15% EtOAc in hexanes) toafford 2-chloro-3-methoxy-5-(trifluoromethyl)pyridine X-28a (0.403 g) asa pale yellow liquid.

Yield: 50%

Basic LCMS Method 2 (ES⁺): 212 (M+H)⁺, 100% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 4.01 (s, 3H) 7.91 (s, 1 H) 8.40 (s, 1H).

Step-2: Synthesis of 3-methoxy-5-(trifluoromethyl)pyridin-2-amine X-28

To a solution of 2-chloro-3-methoxy-5-(trifluoromethyl)pyridine X-28a(0.35 g, 1.65 mmol) in DMSO (10 mL) was added NaN3 (0.33 g, 5.08 mmol)and the reaction mixture was purged with argon for 10 min. Cul (0.09 g,0.46 mmol) and L-Proline (0.09 g, 0.76 mmol) were added and the reactionmixture was heated at 100° C. for 16h. Progress of the reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasdiluted with H₂O (200 mL) and extracted with EtOAc (300 mL). The organiclayer was separated, dried over anhydrous Na₂SO₄ and concentrated undervacuum. The crude obtained was purified by column chromatography(silica, 100-200 mesh, 40% EtOAc in hexanes) to afford3-methoxy-5-(trifluoromethyl)pyridin-2-amine X-28 (0.173 g) as a palebrown solid.

Yield: 54%

Basic LCMS Method 2 (ES⁺): 193 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.84 (s, 3H) 6.54 (brs, 2H) 7.16 (s, 1H)7.84 (s, 1H).

A.29. Synthesis of 3,5-difluoro-6-methoxy-pyridin-2-amine X-29

Step-1: Synthesis of 2-chloro-3-methoxy-5-(trifluoromethyl)pyridineX-28a

To a solution of 2,3,5,6-tetrafluoropyridine (2.00g, 13.2mmo1) inDioxane (100 mL) was added NH₄OH (25% in water, 40 mL). The reactionmixture was heated at 60° C. for 48h. Progress of the reaction wasmonitored by TLC. After completion the reaction mixture was concentratedunder vacuum. The reaction was diluted with H₂O (100 mL) and extractedwith diethyl ether (2×150 mL). The organic layers were separated, driedover anhydrous Na₂SO₄ and concentrated under vacuum to afford 1.30g of3,5,6-trifluoropyridin-2-amine

X-29a as an off white solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 65%

Basic LCMS Method 2 (ES⁻): 147 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.52 (br s, 2 H) 7.85-7.94 (m, 1 H).

Step-2: Synthesis of 3,5-difluoro-6-methoxy-pyridin-2-amine X-29

To a solution 3,5,6-trifluoropyridin-2-amine X-29a (500mg, 3.38mmo1) inmethanol(15mL), sodium methoxide (547mg, 10.1mmol) was added. Thereaction mixture was heated at 90-100° C. for 24h. Progress of thereaction was monitored by TLC. After completion, the reaction mixturewas concentrated under vacuum. The residue was diluted with H₂O (20 mL)and extracted with EtOAc (50 mL). The organic layer was separated, driedover anhydrous Na₂SO₄ and concentrated under vacuum to afford 310mg of3,5-difluoro-6-methoxy-pyridin-2-amine X-29 as an off white solid.

Yield: 52%

Basic LCMS Method 2 (ES⁺): 161 (M+H)⁺, 90% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.81 (s, 3 H) 6.00 (s, 2 H) 7.59 (t, J=10.03Hz, 1 H)

A.30. Synthesis of 3,6-difluoro-5-methyl-pyridin-2-amine X-30

To a stirred solution of 5-bromo-3,6-difluoropyridin-2-amine X-16 (0.40g, 1.91 mmol) in dioxane (12 mL) was added CH3B(OH)2 (0.23 g, 3.82mmol), Na2CO3 (0.51 g, 4.78 mmol) solution in H₂O (3 mL). The reactionmixture was purged with argon for 20 min followed by addition ofPdCl₂(dppf) (0.28 g, 0.38 mmol). The reaction mixture was purged withargon for 10 min and heated at 120° C. for 3h. Progress of reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wascooled to room temperature, filtered through Celite, washed with EtOAc(2×30 mL) and the filtrate was concentrated under vacuum. The crudeobtained was diluted with H₂O (30 mL) and extracted with EtOAc (3×25mL). The organic layer was separated, washed with brine (2×30 mL), driedover anhydrous Na₂SO₄ and concentrated under vacuum. The crude obtainedwas purified by column chromatography (silica, 100-200 mesh, 3% of EtOAcin hexanes) to afford 3,6-difluoro-5-methyl-pyridin-2-amine X-30 (0.145g) as an off-white solid.

Yield: 32%

Basic LC-MS Method 2 (ES⁺): 145 (M+H)⁺, 60% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.79 (s, 3H) 6.39 (s, 2H) 7.63-7.69 (m, 1H).

A.31. Synthesis of 5-bromo-6-fluoro-3-methoxy-pyridin-2-amine X-31

Step 1- Synthesis of 5-bromo-6-fluoro-2-nitro-pyridin-3-ol X-31a

To a solution of H2504 (15 mL) was added KNO3 (0.63 g, 6.28 mmol) andthe reaction mixture was stirred at room temperature for 20 min.5-bromo-6-fluoro-pyridin-3-ol (0.60 g, 3.14 mmol) was added and thereaction mixture was stirred at room temperature for 16h. Progress ofreaction was monitored by TLC. After completion, the reaction mixturewas poured into ice (100 mL) and extracted with EtOAc (3×80 mL). Theorganic layer was separated, washed with brine (120 mL), dried overanhydrous Na₂SO₄ and concentrated under vacuum to afford5-bromo-6-fluoro-2-nitro-pyridin-3-ol X-31a (0.60 g) as an off-whitesolid.

Yield: 56%

¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (d, J=7.2 Hz, 1 H) 11.83 (brs, 1H).

Step 2-Synthesis of 3-bromo-2-fluoro-5-methoxy-6-nitro-pyridine X-31b

To a stirred suspension of NaH (0.11 g, 2.65 mmol) in DMF (8 mL) wasadded 5-bromo-6-fluoro-2-nitro-pyridin-3-ol X-31a (0.60 g, 1.77 mmol inDMF 4 mL) at 0° C. and the reaction mixture was stirred at sametemperature for 30 min. CH31 (0.76 g, 5.32 mmol) was added at 0° C. andthe reaction mixture was stirred at room temperature for 16h. Progressof reaction was monitored by TLC. After completion, the reaction mixturewas quenched with ice, diluted with H₂O (60 mL) and extracted with EtOAc(3 x 40 mL). The organic layer was separated, washed with brine (60 mL),dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crudeobtained was purified by flash column chromatography (12 to 20% EtOAc inhexanes) to afford 3-bromo-2-fluoro-5-methoxy-6-nitro-pyridine X-31b(0.30 g) as a pale yellow liquid.

Yield: 67%

¹H NMR (400 MHz, CDCl₃) δ 4.02 (s, 3H) 7.86 (d, J=6.4 Hz, 1H).

Step 3-Synthesis of 5-bromo-6-fluoro-3-methoxy-pyridin-2-amine X-31

To a solution of 3-bromo-2-fluoro-5-methoxy-6-nitro-pyridine X-31b (0.25g, 1.00 mmol) in CH₃COOH (10 mL) was added Fe (0.45 g, 7.97 mmol) andthe reaction mixture was stirred at room temperature for 2h. Progress ofreaction was monitored by TLC and LCMS. After completion, the reactionmixture was filtered through a pad of celite, washed with EtOAc (220 mL)and filtrate was concentrated under vacuum. The residue was poured intoaqueous saturated NaHCO₃ (150 mL) and extracted with EtOAc (2×125 mL).The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum to afford5-bromo-6-fluoro-3-methoxy-pyridin-2-amine X-31 (0.21 g) as an off-whitesolid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 87%

Basic LC-MS Method 2 (ES⁺): 221 (M-FH)+, 91% purity.

¹H NMR (400 MHz, CDCl₃) δ 3.78 (s, 3H) 6.39 (brs, 2H) 7.32 (d, J=6.8 Hz,1 H).

A.32. Synthesis of 2-(6-amino-2-fluoro-5-methoxy-3-pyridyl)acetonitrileX-32

To a solution of 5-bromo-6-fluoro-3-methoxy-pyridin-2-amine X-31 (0.24g, 1.02 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ypisoxazole (0.24 g, 1.22mmol) in DMSO (12 mL) was added KF (0.18 g, 3.05 mmol) solution in H₂O(3.05 mL). The reaction mixture was purged with argon for 15 minfollowed by addition of PdCl₂(dppf) (0.15 g, 0.20 mmol). The reactionmixture was heated at 120° C. for 16h. Progress of reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasfiltered, filtrate was diluted with brine (40 mL) and extracted withEtOAc (2×70 mL). The organic layer was separated, washed with H₂O (70mL), dried over anhydrous Na₂SO₄ and concentrated under vacuum. Thecrude obtained was purified by flash chromatography (40 to 55% EtOAc inhexanes) to afford 2-(6-amino-2-fluoro-5-methoxy-3-pyridyl)acetonitrileX-32 (0.10 g) as an off-white solid.

Yield: 54%

Basic LC-MS Method 2 (ES⁻): 180 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.77 (s, 5H) 6.24 (brs, 2H) 7.16 (s, 1H).

A.33. Synthesis of 2-(4-amino-2,5-difluoro-phenyl)acetonitrile X-33

4-bromo-2,5-difluoroaniline (300 mg, 1.44 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ypisoxazole (338 mg, 1.731mmol) were placed in dimethyl sulfoxide (10 mL) in a vial. Thenpotassium fluoride (251 mg, 4.326 mmol) and water (78 pL, 4.32 mmol)were added. This suspension was degassed for 10 min of fast argonbubbling in an ultrasound bath. Then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (106 mg,1.144 mmol) was added and the reaction mixture was heated to 120° C.under argon atmosphere for 19 h. It was then filtered over celite andbrine was added to the filtrate which was extracted three times withethyl acetate, dried over magnesium sulfate and evaporated to dryness.The crude residue was purified by column chromatography (SiO₂, 5% to 15%EtOAc in petroleum ether) to afford2-(4-amino-2,5-difluoro-phenyl)acetonitrile X-33 (87 mg) as a lightorange oil.

Yield: 36%

¹H NMR (400 MHz, DMSO-d₆) δ 7.06 (dd, J=11.4, 6.9 Hz, 1 H), 6.58 (dd,J=11.6, 7.5 Hz, 1H), 5.53 (s, 2H), 3.80 (s, 2H).

A.34. Synthesis of 3-(4-amino-2,5-difluoro-phenyl)propanenitrile X-34

Step-1: Synthesis of (2,5-difluoro-4-nitrophenyl)methanol X-34a

2,5-Difluoro-4-nitrobenzoic acid (2.5 g, 12.3 mmol) was placed in drytetrahydrofuran (10 mL) under argon atmosphere. Then triethylamine (1.7mL, 12.3 mmol) was added and the solution was cooled to 0° C. A solutionof ethyl chloroformate (1.2 mL, 12.9 mmol) in dry tetrahydrofuran (15mL) was added over 15 min and the reaction mixture was stirred overnightat room temperature. The precipitated triethylammonium chloride wasfiltered off and, while stirring, sodium borohydride (1.4 g, 3.69 mmol)was added portionwise to the filtrate. Next, methanol (15 mL) was addeddropwise and the reaction mixture was stirred overnight at roomtemperature. It was then acidified with 1N HCI until pH=2 and thetetrahydrofuran was removed under vacuum. The residue was taken up inethyl acetate and washed with a saturated sodium hydrogen carbonatesolution. The aqueous phase was then extracted three times with ethylacetate. The combined organic phases were washed with brine, dried overmagnesium sulfate and evaporated to dryness. The crude residue waspurified by column chromatography (SiO₂, DCM) to afford(2,5-difluoro-4-nitrophenyl)methanol X-34a (1.61 g) as an orange solid.

Yield: 70%.

¹H NMR (400 MHz, DMSO-d₆) δ 7.77 (dd, J=8.8, 5.8 Hz, 1H), 7.51 (dd,J=11.0, 5.7 Hz, 1H), 4.86 (s, 2H), 2.19 (s, 1H).

Step-2: Synthesis of 2,5-difluoro-4-nitrobenzaldehyde X-34b

(2,5-Difluoro-4-nitrophenyl)methanol X-34a (320 mg, 1.69 mmol) wasstirred in dichloromethane (10 mL) with activated manganese oxide (163g, 169.2 mmol) at room temperature. After two days the reaction mixturewas filtered over celite and evaporated to dryness to afford2,5-difluoro-4-nitrobenzaldehyde X-34b (231 mg) as an orange solid.

Yield: 73%.

¹H NMR (400 MHz, DMSO-d₆) δ 10.36 (d, J=2.6 Hz, 1H), 7.93 (dd, J=8.7,5.4 Hz, 1H), 7.80 (dd, J=9.7, 5.4 Hz, 1 H).

Step-3: Synthesis of (E)-3-(2,5-difluoro-4-nitrophenyl)acrylonitrileX-34c

Diethyl cyanomethylphosphonate (227 mg, 1.238 mmol) was placed in drytetrahydrofuran (2 mL) under argon atmosphere. At 0° C., sodium hydride(60% dispersion in mineral oil, 77 mg, 1.925 mmol) was added. Themixture was stirred for 15 min at room temperature and2,5-difluoro-4-nitrobenzaldehyde X-34b (240 mg, 1.238 mmol) in solutionin dry tetrahydrofuran (3 mL) was added slowly at 0° C. After 1.5 h, thereaction mixture was quenched with a saturated sodium hydrogen carbonatesolution. The product was next extracted with ethyl acetate, and theorganic phase was washed once with a saturated sodium hydrogen carbonatesolution. The combined aqueous layers were extracted three times withethyl acetate. The combined organic phases were washed brine, dried overmagnesium sulfate and evaporated to dryness. The crude residue waspurified by column chromatography (SiO₂, CombiFlash 24 g, 2% to 15%EtOAc in petroleum ether) to afford the desired product(E)-3-(2,5-difluoro-4-nitrophenyl)acrylonitrile X-34c (40 mg) as ayellow solid.

Yield: 15%.

¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (dd, J=9.8, 6.2 Hz, 1H), 8.11 (dd,J=11.8, 5.9 Hz, 1H), 7.72 (d, J=16.7 Hz, 1H), 6.77 (d, J=16.7 Hz, 1H).

Step-4: Synthesis of 3-(4-amino-2,5-difluoro-phenyl)propanenitrile X-34

(E)-3-(2,5-Difluoro-4-nitrophenyl)acrylonitrile X-34c (65 mg, 0.309mmol) was dissolved in absolute ethanol (8 mL) under argon atmosphere.Then palladium on carbon (10 wt. % loading, 16 mg, 0.015 mmol) was addedand the flask was flushed with argon, and then hydrogen. The reactionmixture was stirred for 4 h under hydrogen atmosphere. It was thenfiltered over celite and evaporated to dryness. The crude residue waspurified by column chromatography (SiO₂, CombiFlash 4 g, 2% to 20% EtOAcin petroleum ether) to afford3-(4-amino-2,5-difluoro-phenyl)propanenitrile X-34 (35 mg) as a yellowoil that crystalizes on standing.

Yield: 63%.

¹H NMR (400 MHz, DMSO-d₆) δ 7.01 (dd, J=11.7, 6.9 Hz, 1H), 6.52 (dd,J=11.6, 7.6 Hz, 1H), 5.34 (br s, 2H), 2.75-2.69 (m, 4H).

A.35. Synthesis of 3,6-difluoro-5-(2-fluoroethoxy)pyridin-2-amine X-

Step-1: Synthesis of5-bromo-3,6-difluoro-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amineX-35a

To a solution of 5-bromo-3,6-difluoropyridin-2-amine X-16 (4.00 g, 19.0mmol) in DMAC (40 mL) was added NaH (2.29 g, 57.1 mmol) portion wise at0° C. and the reaction was stirred at the same temperature for 30 min.Para-methoxybenzyl chloride (5.19 mL, 38.1 mmol) was added dropwise at0° C. and the reaction mixture was stirred at room temperature for 2h.Progress of the reaction was monitored by TLC. After completion, thereaction mixture was cooled to 0° C., quenched with saturated NH₄Cl (20mL), poured into H₂O (60 mL) and extracted with EtOAc (3×60 mL). Theorganic layer was separated, washed with brine (2 x 80 mL), dried overanhydrous Na₂SO₄ and concentrated under vacuum. The crude obtained waspurified by column chromatography (silica, 100-200 mesh, 4% EtOAc inhexanes) to afford5-bromo-3,6-difluoro-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amineX-35a (8.2 g, 96%) as an off-white solid.

Yield: 96%.

¹H NMR (400 MHz, DMSO-d₆) δ 3.72 (s, 6H) 4.57 (s, 4H) 6.87-6.89 (m, 4H)7.16-7.18 (m, 4H) 7.99 -8.07 (m, 1 H).

Step-2: Synthesis of3,6-difluoro-N,N-bis[(4-methoxyphenyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amineX-35b

To a solution of5-bromo-3,6-difluoro-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amineX-35a (4.00 g, 8.90 mmol) in dioxane (160 mL) was addedBis(pinacolato)diboron (4.52 g, 17.8 mmol) and KOAc (3.06 g, 31.2 mmol)at room temperature and the reaction mixture was purged with argon for20 min followed by addition of PdCl₂(dppf) (0.65 g, 0.89 mmol). Thereaction mixture was purged with argon for 10 min and heated at 100° C.for 16h. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was cooled, filtered through a pad ofcelite and washed with EtOAc (2×80 mL). The filtrate was concentratedunder vacuum, the residue was diluted with H₂O (100 mL) and extractedwith EtOAc (2×80 mL). The organic layer was separated, washed with brine(2×100 mL), dried over anhydrous Na₂SO₄ and concentrated under vacuum.The crude obtained was purified by column chromatography (silica,100-200 mesh, 8% EtOAc in hexanes) to afford3,6-difluoro-N,N-bis[(4-methoxyphenyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amineX-35b (2.60 g) as an off-white solid.

Yield: 59%.

¹H NMR (400 MHz, DMSO-d₆) δ 1.26 (s, 12H) 3.73 (s, 6H) 4.64 (s, 4H) 6.89(d, J=8.31 Hz, 4H) 7.17 (d, J=8.80 Hz, 4H) 7.51-7.56 (m, 1H).

Step-3: Synthesis of6-[bis[(4-methoxyphenyl)methyl]amino]-2,5-difluoro-pyridin-3-ol X-35c

To a solution of3,6-difluoro-N,N-bis[(4-methoxyphenyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amineX-35b (2.50 g, 5.04 mmol) in THF (30 mL) was added 30% H₂O₂ solution inH₂O (10 mL) at 0° C. and the reaction mixture was stirred at sametemperature for 15 min. The reaction mixture was stirred at roomtemperature for 1.5h. Progress of the reaction was monitored by TLC andLCMS. The reaction mixture was poured into 5% Na₂S₂O₃ solution in coldH₂O (250 mL) at 0° C., diluted with H₂O (100 mL) and extracted withEtOAc (2×100 mL). The organic layer was separated, dried over anhydrousNa₂SO₄ and concentrated under vacuum to afford6-[bis[(4-methoxyphenyl)methyl]amino]-2,5-difluoro-pyridin-3-ol X-35c(1.74 g crude) as a yellow semi solid.

This compound was used as such for the next reaction without furtherpurification.

Basic LC-MS Method 2 (ES⁺): 387 (M-FH)+, 93% purity.

¹H NMR (400 MHz, DMSO-d6) δ 3.71 (s, 6H) 4.32 (s, 4H) 6.86 (d, J=8.80Hz, 4H) 7.14 (d, J=8.31 Hz, 4H) 7.22-7.27 (m, 1 H) 9.84 (s, 1 H).

Step-4: Synthesis of3,6-difluoro-5-(2-fluoroethoxy)-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amineX-35d

To a solution of6-[bis[(4-methoxyphenyl)methyl]amino]-2,5-difluoro-pyridin-3-ol X-35c(0.70 g, 1.68 mmol) in DMF (13 mL) was added K₂CO₃ (0.70 g, 5.04 mmol)and 1-bromo-2-fluoroethane (0.43 g, 3.36 mmol) at room temperature. Thereaction mixture was heated in microwave at 80° C. for 15 min. Progressof the reaction was monitored by TLC and LCMS. After completion, thereaction mixture was cooled to room temperature, poured into H₂O (30 mL)and extracted with EtOAc (3×25 mL). The organic layer was separated,washed with brine (2×30 mL), dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude obtained was purified by columnchromatography (silica, 100-200 mesh, 25% EtOAc in hexanes) to afford3,6-difluoro-5-(2-fluoroethoxy)-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amineX-35d (0.52 g) as a brown liquid.

Yield: 71%.

Basic LC-MS Method 2 (ES⁺): 433 (M-FH)+, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.72 (s, 6H) 4.21-4.25 (m, 1 H) 4.29-4.32(m, 1H) 4.42 (s, 4H) 4.63-4.66 (m, 1H) 4.75-4.78 (m, 1H) 6.87 (d, J=8.86Hz, 4H) 7.15 (d, J=8.37 Hz, 4H) 7.69-7.76 (m, 1H).

Step-5: Synthesis of 3,6-difluoro-5-(2-fluoroethoxy)pyridin-2-amine X-35

To3,6-difluoro-5-(2-fluoroethoxy)-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amineX-35d (0.50 g, 1.15 mmol) was added TFA (5 mL) at 0° C. and the reactionmixture was stirred at same temperature for 30 min. The reaction mixturewas stirred at room temperature for 2h. Progress of the reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasconcentrated under vacuum. The residue was diluted with H₂O (25 mL),basified with aqueous NaHCO₃ solution (10 mL) and extracted with EtOAc(2×25 mL). The organic layer was separated, washed with brine (2×40 mL),dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crudeobtained was purified by triturating with Et2O (10 mL) and dried undervacuum to afford 3,6-difluoro-5-(2-fluoroethoxy)pyridin-2-amine X-35(0.258 g) as an off-white solid.

Yield: 80%.

Basic LC-MS Method 2 (ES⁺): 193 (M-FH)+, 69% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 4.13-4.17 (m, 1H) 4.20-4.25 (m, 1H)4.59-4.64 (m, 1H) 4.71-4.76 (m, 1 H) 6.10 (s, 2H) 7.57-7.62 (m, 1H).

A.36. Synthesis of 3,6-difluoro-5-(2-methoxyethoxy)pyridin-2-amine X-36

Step-1: Synthesis of3,6-difluoro-5-(2-methoxyethoxy)-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amineX-36a

To a solution of6-[bis[(4-methoxyphenyl)methyl]amino]-2,5-difluoro-pyridin-3-ol X-35c(0.60 g, 1.44 mmol) and 2-bromoethyl methyl ether (0.70 g, 5.04 mmol) inDMF (10 mL) was added K₂CO₃ (0.90 g, 6.48 mmol) and the reaction mixturewas heated in microwave at 80° C. for 30 min. The reaction mixture wasstirred at room temperature for 16h. Progress of the reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasdiluted with H₂O (100 mL) and extracted with EtOAc (200 mL). The organiclayer was separated, dried over anhydrous Na₂SO₄ and concentrated undervacuum. The crude obtained was purified by column chromatography(silica, 100-200 mesh, 2% EtOAc in hexanes) to afford3,6-difluoro-5-(2-methoxyethoxy)-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amineX-36a (0.205 g) as a brown semi solid.

Yield: 31%.

Basic LC-MS Method 2 (ES⁺): 445 (M+H)⁺, 96% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.28 (s, 3H) 3.59-3.63 (m, 2H) 3.71 (s, 6H)4.09-4.14 (m, 2H) 4.40 (s, 4H) 6.85-6.89 (m, 4H) 7.15 (d, J=8.31 Hz, 4H)7.66-7.71 (m, 1H).

Step-2: Synthesis of 3,6-difluoro-5-(2-methoxyethoxy)pyridin-2-amineX-36

To3,6-difluoro-5-(2-methoxyethoxy)-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amineX-36a (0.20 g, 0.43 mmol) was added TFA (6 mL) at 0° C. and the reactionmixture was stirred at room temperature for 2h. Progress of the reactionwas monitored by TLC. After completion, the reaction mixture wasconcentrated under vacuum. The residue was diluted with H₂O (100 mL),basified with saturated NaHCO₃ solution (50 mL) and extracted with EtOAc(200 mL). The organic layer was separated, dried over anhydrous Na₂SO₄and concentrated under vacuum to afford3,6-difluoro-5-(2-methoxyethoxy)pyridin-2-amine X-36 (0.15 g crude) as abrown semi solid.

This compound was used as such for the next reaction without furtherpurification.

¹H NMR (400 MHz, DMSO-d₆) δ 3.29 (s, 3H) 3.53-3.59 (m, 2H) 4.00-4.04 (m,2H) 6.01 (s, 2H) 7.51-7.57 (m, 1 H).

B. Synthesis of intermediates of Formula XI B.1. Synthesis of6-cyclopropyl-1H-indole XI-1

Step 1: Synthesis of tert-butyl 6-bromoindole-1-carboxylate XI-la:

To a solution of 6-bromo-1 H-indole (2.70 g, 13.8 mmol) in THF (30 mL)was added triethylamine (2.80 g, 27.6 mmol) at 0° C. and the reactionmixture was stirred at same temperature for 5 min. DMAP (0.84 g, 6.90mmol) and (Boc)₂O (4.50 g, 20.7 mmol) were added at 0° C. and thereaction mixture was stirred at room temperature for 3h. Progress of thereaction was monitored by TLC. After completion, the reaction mixturewas quenched with ice and concentrated under vacuum. The residue wasdiluted with H₂O (100 mL) and extracted with EtOAc (3×100 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude obtained was purified by columnchromatography (silica, 100-200 mesh, 1% EtOAc in hexanes) to afford 3.8g of tert-butyl 6-bromoindole-1-carboxylate XI-1a as a light yellowsolid.

Yield: 92%.

¹H NMR (400 MHz, DMSO-d₆) δ 1.65 (s, 9H) 6.73 (d, J=3.42 Hz, 1H)7.20-7.27 (m, 1H) 7.60 (d, J=8.31 Hz, 1H) 7.69 (d, J=3.42 Hz, 1 H) 8.23(s, 1 H).

Step-2: Synthesis of tert-butyl 6-cyclopropylindole-1-carboxylate XI-1 b

To a solution of tert-butyl 6-bromoindole-1-carboxylate XI-1a (0.70 g,2.36 mmol) and cyclopropylboronic acid (0.30 g, 3.55 mmol) in toluene(15 mL) was added K3PO4 (1.00 g, 4.72 mmol), tricyclohexylphosphine(PCy3) (0.13 g, 0.47 mmol) and H₂O (0.70 mL). The reaction mixture waspurged with argon for 15 min followed by addition of Pd(OAc)₂ (0.05 g,0.24 mmol). The reaction mixture was heated at 100° C. for 8h. Progressof the reaction was monitored by TLC. After completion, the reactionmixture was diluted with H₂O (20 mL) and extracted with EtOAc (2×20 mL).The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated in vacuum. The crude obtained was purified by columnchromatography (silica, 100-200 mesh, 0.5 to 0.8% EtOAc in hexanes) toafford 0.5 g of tert-butyl 6-cyclopropylindole-1-carboxylate XI-1 b as acolourless liquid.

Yield: 83%.

¹H NMR (400 MHz, CDCl₃) δ 0.70-0.78 (m, 2H) 0.96-1.03 (m, 2H) 1.67 (s,9H) 1.98 -2.10 (m, 1H) 6.50 (s, 1H) 6.99 (d, J=7.82 Hz, 1H) 7.42 (d,J=8.31 Hz, 1H) 7.50 (d, J=3.42 Hz, 1H) 7.90 (brs, 1H).

Step-3: Synthesis of 6-cyclopropyl-1 H-indole XI-1

To a solution of tert-butyl 6-cyclopropylindole-1-carboxylate XI-1b(1.30 g, 5.10 mmol) in DCM (25 mL) was added TFA (2.5 mL) dropwise at 0°C. The reaction mixture was stirred at room temperature for 3h. Progressof the reaction was monitored by TLC. After completion, the reactionmixture was concentrated in vacuum. The residue was diluted with DCM (80mL) and neutralised with triethylamine (4 mL) at 0° C. The organic layerwas separated, washed with cold brine (20 mL), dried over anhydrousNa₂SO₄ and concentrated in vacuum. The crude obtained was purified bycolumn chromatography (silica, 100-200 mesh, 4 to 5% EtOAc in hexanes)to afford 0.32 g of 6-cyclopropyl-1H-indole XI-1 as a colourless liquid.

Yield: 41%.

¹H NMR (400 MHz, CDCl₃) δ 0.71-0.76 (m, 2H) 0.93-1.00 (m, 2H) 1.98-2.08(m, 1H) 6.51 (s, 1H) 6.90 (d, J=8.31 Hz, 1H) 7.13-7.18 (m, 2H) 7.52-7.58(m, 1H) 8.03 (brs, 1H).

B.2. Synthesis of 6-chloro-benzofuran XI-2

Step-1: Synthesis of methyl 4-chloro-2-(2-ethoxy-2-oxoethoxy)benzoateXI-2a

To a solution of methyl 4-chloro-2-hydroxy-benzoate (5.00 g, 26.7 mmol)in acetone (60 mL) was added ethyl-2-bromo acetate (6.72 g, 40.2 mmol)and K₂CO₃ (5.56 g, 40.2 mmol). The reaction mixture was heated to refluxfor 16h. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was concentrated under vacuum. Theresidue was dissolved in petroleum ether (80 mL), filtered and thefiltrate was concentrated under vacuum. The crude obtained was purifiedby column chromatography (silica, 100-200 mesh, 20% EtOAc in hexanes) toafford methyl 4-chloro-2-(2-ethoxy-2-oxoethoxy)benzoate XI-2a (6.80 g)as a red semi solid.

The product was confirmed by TLC analysis only.

Yield: 93%.

Step-2: Synthesis of 2-(5-chloro-2-(methoxycarbonyl)phenoxy)acetic acidXI-2b

To a solution of XI-2a (6.80 g, 24.9 mmol) in MeOH (180 mL) was addedKOH (3.13 g, 55.8 mmol) solution in H₂O (40 mL) at 0° C. and thereaction mixture was stirred at room temperature for 2h. Progress of thereaction was monitored by TLC and LCMS. After completion, the reactionmixture was concentrated under vacuum. The residue was dissolved in H₂O(100 mL) and acidified to pH 2 with 2N HCI. The precipitated solid wasfiltered, dried under vacuum to afford2-(5-chloro-2-(methoxycarbonyl)phenoxy)acetic acid XI-2b (3.80 g) as awhite solid.

Yield: 66%.

Basic LCMS Method 2 (ES⁺): 245.00 (M+H)⁺, 16% purity.

Step-3: Synthesis of 6-chlorobenzofuran-3-yl acetate XI-2c

To a solution of XI-2b (3.80 g, 16.4 mmol) in CH₃COOH (75 mL) was addedAc2O (95 mL) followed by addition of NaOAc (3.19 g, 37.7 mmol). Thereaction mixture was heated at 140° C. for 5h. Progress of the reactionwas monitored by TLC. After completion, the reaction mixture was dilutedwith H₂O (300 mL) and extracted with EtOAc (60 mL). The organic layerwas separated, washed with saturated NaHCO₃ (20 mL), dried overanhydrous Na₂SO₄ and concentrated under vacuum to afford6-chlorobenzofuran-3-yl acetate XI-2c (3.00 g, 87%) as a red liquid.

This compound was used as such for the next reaction without furtherpurification.

¹H NMR (400 MHz, DMSO-d₆) δ 2.37 (s, 3H) 7.34-7.40 (m, 1H) 7.60 (s, 1H)7.78-7.82 (m, 1H) 8.24 (s, 1H).

Step-4: Synthesis of 6-chlorobenzofuran-3(2H)-one XI-2d

To a solution of XI-2c (3.00 g, 1.42 mmol) in MeOH (150 mL) was addedconcentrated. HCI (4 mL) and H₂O (35 mL) and the reaction mixture washeated at reflux for 3h. Progress of the reaction was monitored by TLC.After completion, the reaction mixture was cooled to room temperature,diluted with H₂O (20 mL) and filtered. The crude obtained was washedwith H₂O (20 mL) and dried under vacuum to afford6-chlorobenzofuran-3(2H)-one XI-2d (2.20 g, 92%) as a red solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.34 (s, 2H) 7.23 (d, J=7.83 Hz, 1 H) 7.38(d, J=7.83 Hz, 1 H) 7.70 (t, J=9.05 Hz, 1 H).

Step-5: Synthesis of 6-chlorobenzofuran XI-2

To a solution of XI-2d (2.20 g, 13.0 mmol) in MeOH (75 mL) was addedNaBH4 (1.08 g, 28.7 mmol) portion wise at 0° C. The reaction mixture wasstirred at room temperature for 4h. Progress of the reaction wasmonitored by TLC. After completion, the reaction mixture was quenchedwith acetone (20 mL), diluted with 3 N HCI (35 mL) and stirred for 1h.The reaction mixture was extracted with EtOAc (50 mL), dried overanhydrous Na₂SO₄ and concentrated under vacuum to afford6-chlorobenzofuran XI-2 (1.60 g) as a colourless liquid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 80%.

¹H NMR (400 MHz, DMSO-d₆) δ 6.99 (d, J=0.98 Hz, 1H) 7.30 (d, J=8.31 Hz,1H) 7.67 (d, J=8.31 Hz, 1 H) 7.77 (s, 1H) 8.04 (d, J=1.96 Hz, 1 H).

B.3. Synthesis of 6-(2-methoxyethoxy)-1H-indole XI-3

A solution of 1 H-indol-6-ol (0.95 g, 7.12 mmol) in DMF (12 mL) wastreated with cesium carbonate (2.79 g, 8.59 mmol) and stirred at 75 ° C.for 16 h (TLC control). Subsequently, the solvent was evaporated and theresidue was diluted with ethyl acetate, washed with 1 N NaOH solution,water and brine. The combined organic extracts were dried over MgSO₄,filtered and evaporated. The residue was purified by columnchromatography (cyclohexane/ethyl acetate=4:1) and afforded 0.88g of6-(2-methoxyethoxy)-1H-indole XI-3 as a white solid.

Yield: 65%.

Neutral LCMS Method 3 (ES⁺): 192.0 (M+H)⁺, 96% purity.

B.4. Synthesis of 6-chloro-7-methoxy-1H-indole XI-4

To a solution of 1-chloro-2-methoxy-3-nitro-benzene (1.00 g, 5.34 mmol)in THF (20 mL) was added vinyl magnesium bromide (16.0 mL, 16.0 mmol) at-20° C. and the reaction mixture was stirred at room temperature for 3h.Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was quenched with ice and extractedwith EtOAc (100 mL). The organic layer was separated, dried overanhydrous Na₂SO₄ and concentrated under vacuum. The crude obtained waspurified by column chromatography (silica, 100-200 mesh, 5 to 10% EtOAcin hexanes) to afford 6-chloro-7-methoxy-1H-indole XI-4 (0.50 g) as aviscous oil.

Yield: 51%

¹H NMR (400 MHz, DMSO-d₆) δ 3.91 (s, 3H) 6.47 (s, 1H) 6.99 (d, J=8.40Hz, 1H) 7.29 (d, J=8.00 Hz, 1 H) 7.35 (s, 1H) 11.46 (brs, 1H).

B.5. Synthesis of 6-chloro-7-fluoro-IH-indole XI-5

To a solution of 1-chloro-2-fluoro-3-nitro-benzene (2.50 g, 14.2 mmol)in THF (50 mL) was added vinyl magnesium bromide (5.61 g, 42.7 mmol) at-78° C. and the reaction mixture was stirred at same temperature for 1h. Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was quenched with saturated NH4C1 (100mL), diluted with H₂O (400 mL) and extracted with EtOAc (500 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude obtained was purified by columnchromatography (silica, 100-200 mesh, 5% EtOAc in hexanes) to affordafford 6-chloro-7-fluoro-1 H-indole XI-5 (0.60 g) as a red liquid.

Yield: 17%

Basic LCMS Method 2 (ES⁻): 168.00 (M−H)⁻, 66% purity.

B.6. Synthesis of 6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine XI-6

Step-1: Synthesis of 7-oxido-1H-pyrrolo[2,3-b]pyridin-7-ium XI-6a

To a solution of 1 H-pyrrolo[2,3-b]pyridine (2.00 g, 16.9 mmol) in Et₂O(50 mL) was added m-CPBA (3.80 g, 22.0 mmol) portion wise at 5° C. andthe reaction mixture was stirred at room temperature for 2h. Progress ofthe reaction was monitored by TLC and LCMS. After completion, thereaction mixture was filtered, washed with Et₂O (12 mL) and dried undervacuum to afford 7-oxido-1 H-pyrrolo[2,3-b]pyridin-7-ium XI-6a (3.75 g)as an off-white solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 89%

Basic LCMS Method 2 (ES⁺): 135 (M+H)⁺, 54% purity.

Step-2: Synthesis of methyl 6-iodopyrrolo[2,3-b]pyridine-1-carboxylateXI-6b

To a solution of 7-oxido-1H-pyrrolo[2,3-b]pyridin-7-ium XI-6a (1.60 g,11.9 mmol) in THF (100 mL) was added hexamethyldisilazane (2.31 g, 14.3mmol) and trimethylsilyl iodide (4.77 g, 23.9 mmol) dropwise followed bydropwise addition of methyl chloroformate (2.25 g, 23.9 mmol). Thereaction mixture was stirred at room temperature for 5h. Progress of thereaction was monitored by TLC and LCMS. After completion, the reactionmixture was concentrated under vacuum. The residue was diluted withEtOAc (150 mL) and washed with saturated NaHCO₃ (100 mL). The organiclayer was separated, dried over anhydrous Na₂SO₄ and concentrated undervacuum. The crude obtained was purified by column chromatography(silica, 100-200 mesh, 10% EtOAc in hexanes) to afford methyl6-iodopyrrolo[2,3-b]pyridine-1-carboxylate XI-6b (1.00 g) as a brownsolid.

Yield: 26%

Basic LCMS Method 2 (ES⁺): 303 (M+H)⁺, 95% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 4.12 (s, 3H) 6.55 (d, J=3.91 Hz, 1H)7.54-7.58 (m, 1H) 7.61-7.65 (m, 1H) 7.69 (d, J=3.91 Hz, 1H).

Step-3: Synthesis of methyl6-(trifluoromethyl)pyrrolo[2,3-b]pyridine-1-carboxylate XI-6c

To a solution of methyl 6-iodopyrrolo[2,3-b]pyridine-1-carboxylate XI-6b(1.00 g, 3.14 mmol) in DMF (16.7 mL) was added methyl2,2-difluoro-2-fluorosulfonyl-acetate (2.41 g, 12.6 mmol) and Cul (0.12g, 0.62 mmol) and the reaction mixture was heated at 115° C. for 4h.Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was diluted with EtOAc (60 mL). Theorganic layer was separated, washed with H₂O (25 mL), NH4CI (25 mL) andbrine (25 mL), dried over anhydrous Na₂SO₄ and concentrated undervacuum. The crude obtained was purified by column chromatography(silica, 100-200 mesh, 10% EtOAc in hexanes) to afford methyl6-(trifluoromethyl)pyrrolo(trifluoromethyl)pyrrolo[2,3-b]pyridine-1-carboxylate XI-6c (0.65 g) asan off-white solid.

Yield: 71%

Basic LCMS Method 2 (ES⁺): 245 (M+H)⁺, 84% purity.

¹H NMR (400 MHz, CHLOROFORM-d) δ 4.14 (s, 3H) 6.68 (d, J=3.42 Hz, 1H)7.63 (d, J=8.31 Hz, 1 H) 7.94 (d, J=2.93 Hz, 1H) 8.06 (d, J=7.83 Hz, 1H).

Step-4: Synthesis of 6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine XI-6

To a solution of methyl6-(trifluoromethyl)pyrrolo[2,3-b]pyridine-1-carboxylate XI-6c (0.65 g,2.23 mmol) in MeOH (33 mL) was added 1 M NaOH (0.26 g, 6.68 mmol)solution and the reaction mixture was stirred at room temperature for16h. Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was concentrated under vacuum. Theresidue was extracted with DCM (3×15 mL). The organic layer wasseparated, dried over anhydrous Na₂SO₄ and concentrated under vacuum toafford 6-(trifluoromethyl)-1 H-pyrrolo[2,3-b]pyridine XI-6 (0.45 g) asan off-white solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 97%

Basic LCMS Method 2 (ES⁺): 187 (M+H)⁺, 89% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.61 (t, J=2.00 Hz, 1H) 7.52 (d, J=7.82 Hz,1H) 7.77 (t, J=2.93 Hz, 1H) 8.21 (d, J=8.31 Hz, 1H) 12.16 (brs, 1H).

B.7. Synthesis of 7-bromo-6-chloro-1H-indole XI-7

To a solution of 2-bromo-1-chloro-3-nitro-benzene (4.50 g, 19.0 mmol) inTHF (90 mL) was added vinyl magnesium bromide (9.99 g, 76.1 mmol)dropwise at -78° C. and the reaction mixture was stirred at the sametemperature for 2h. Progress of the reaction was monitored by TLC andLCMS. The reaction was repeated at 4.5 g scale and the crude mixture of2 reactions was clubbed. After completion, the reaction mixture wasquenched with saturated NH₄Cl (500 mL), diluted with H₂O (500 mL) andextracted with EtOAc (1000 mL). The organic layer was separated, driedover anhydrous Na₂SO₄ and concentrated under vacuum. The crude obtainedwas purified by column chromatography (silica, 100-200 mesh, 2% EtOAc inhexanes) to afford 7-bromo-6-chloro-1 H-indole XI-7 (3.05 g) as a yellowsolid.

Yield: 33%

Basic LCMS Method 2 (ES⁻): 228.00 (M−H)⁻, 96% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.59 (d, J=1.96 Hz, 1H) 7.18 (d, J=8.31 Hz,1H) 7.41-7.45 (m, 1 H) 7.57 (d, J=8.31 Hz, 1H) 11.48 (brs, 1 H)

B.8. Synthesis of 6-chloro-7-(2,2-difluoroethoxy)-1H-indole XI-8

Step-1: Synthesis of 1-chloro-2-(2,2-difluoroethoxy)-3-nitrobenzeneXI-8a

To a solution of 2-chloro-6-nitro-phenol (0.50 g, 2.88 mmol) in toluene(15 mL) was added 2,2-difluoroethanol (0.37 mL, 5.76 mmol) followed byaddition of (cyanomethylene)tributylphosphorane (0.91 mL, 3.46 mmol).The reaction mixture was heated at 90° C. for 16h. Progress of thereaction was monitored by TLC and LCMS. After completion, the reactionmixture was diluted with H₂O (50 mL) and extracted with EtOAc (3×25 mL).The organic layer was separated, washed with brine (30 mL), dried overanhydrous Na₂SO₄ and concentrated under vacuum. The crude obtained waspurified by column chromatography (silica, 100-200 mesh, 10% EtOAc inhexanes) to afford 1-chloro-2-(2,2-difluoroethoxy)-3-nitrobenzene XI-8a(0.60 g) as a pale yellow solid.

Yield: 86%

¹H NMR (400 MHz, DMSO-d₆) δ 4.39-4.43 (m, 2H) 6.21- 6.53 (m, 1H)7.41-7.47 (m, 1H) 7.90-7.94 (m, 1H) 7.98 (dd, J=8.31, 1.47 Hz, 1H).

Step-2: Synthesis of 6-chloro-7-(2,2-difluoroethoxy)-1 H-indole XI-8

To a solution of 1-chloro-2-(2,2-difluoroethoxy)-3-nitrobenzene XI-8a(0.60 g, 2.46 mmol) in THF (40 mL) was added 1 M vinylmagnesium bromide(1.29 g, 9.86 mmol) dropwise at −78° C. and the reaction mixture wasstirred at same temperature for 1 h. The reaction mixture was thenstirred at −40° C. for 1 h. Progress of the reaction was monitored byTLC and LCMS. After completion, the reaction mixture was quenched withsaturated NH₄C1 (35 mL) and extracted with EtOAc (2×50 mL). The organiclayer was separated, dried over anhydrous Na₂SO₄ and concentrated undervacuum. The crude obtained was purified by column chromatography(silica, 100-200 mesh, 10% EtOAc in hexanes) to afford6-chloro-7-(2,2-difluoroethoxy)-1 H-indole XI-8 (0.13 g) as a paleyellow solid.

Yield: 23%

Basic LCMS Method 2 (ES⁻): 230 (M−H)⁻, 67% purity.

B.9. Synthesis of 6-chlorobenzothiophene XI-9

Step-1: Synthesis of ethyl 6-chlorobenzothiophene-2-carboxylate XI-9a

To a solution of 4- chloro-2-fluorobenzaldehyde (10.0 g, 63.0 mmol) inDMF (100 mL) was added ethyl thioglycolate (11.3 g, 94.6 mmol) followedby addition of K₂CO₃ (26.1 g, 189 mmol). The reaction mixture was heatedat 70° C. for 16h. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was diluted with H₂O (300 mL) andextracted with EtOAc (2×300 mL). The organic layer was separated, driedover anhydrous Na₂SO₄ and concentrated under vacuum to afford ethyl6-chlorobenzothiophene-2-carboxylate XI-9a (9.10 g) as an off-whitesolid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 60%

¹H NMR (400 MHz, DMSO-d₆) δ 1.33 (t, J=7.09 Hz, 3H) 4.35 (q, J=7.01 Hz,2H) 7.51 (dd,

J=8.56, 1.71 Hz, 1H) 8.04 (d, J=8.80 Hz, 1H) 8.20 (s, 1H) 8.25 (d,J=0.98 Hz, 1H).

Step-2: Synthesis of 6-chlorobenzothiophene-2-carboxylic acid XI-9b

To a solution of ethyl 6-chlorobenzothiophene-2-carboxylate XI-9a (9.00g, 37.5 mmol) in EtOH was added 3 N NaOH (24.9 mL, 74.7 mmol) and thereaction mixture was stirred at room temperature for 16h. Progress ofthe reaction was monitored by TLC. After completion, the reactionmixture was concentrated under vacuum. The residue was diluted with H₂O(200 mL), acidified with 2 N HCI and extracted with EtOAc (2×300 mL).The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum to afford 6-chlorobenzothiophene-2-carboxylicacid XI-9b (6.10 g) as an off-white solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 77%

¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (d, J=8.31 Hz, 2H) 8.10 (s, 1H) 8.21(s, 1H) 13.52 (brs, 1H).

Step-3: Synthesis of 6-chlorobenzothiophene XI-9

To a solution of 6-chlorobenzothiophene-2-carboxylic acid XI-9b (1.00 g,4.70 mmol) in DMA (5 mL) was added DBU (2.86 g, 18.8 mmol) and reactionmixture was heated in microwave at 200° C. for 1 h. Progress of thereaction was monitored by TLC. After completion, the reaction mixturewas diluted with H₂O (30 mL) and extracted with EtOAc (3×20 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum to afford 6-chlorobenzothiophene XI-9 (0.51 g)as an off-white white solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 65%

¹H NMR (400 MHz, DMSO-d₆) δ 7.41 (dd, J=8.56, 1.71 Hz, 1H) 7.47 (d,J=5.38 Hz, 1H) 7.80 (d, J=5.38 Hz, 1H) 7.89 (d, J=8.80 Hz, 1H) 8.17 (d,J=0.98 Hz, 1H).

B.10. Synthesis of 6-chloro-5,7-difluoro-1H-indole XI-10

To a solution of 2-chloro-1,3-difluoro-4-nitro-benzene (6 g, 31 mmol) inTHF (120 mL) was added vinyl magnesium bromide (105 mL, 1M, 105 mmol)dropwise at -78° C. and the reaction mixture was stirred at the sametemperature for 2h. Progress of the reaction was monitored by TLC andLCMS. After completion, the reaction mixture was quenched with saturatedNH₄Cl (200 mL), diluted with H₂O (300 mL) and extracted with EtOAc (500mL).

The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude obtained was purified by columnchromatography (silica, 100-200 mesh, 10% EtOAc in hexanes) to afford6-chloro-5,7-difluoro-1H-indole XI-10 (0.71 g) as a brown solid.

Yield: 12%

Basic LCMS Method 2 (ES⁻): 186 (M−H)⁻, 96% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.54-6.60 (m, 1 H) 7.44 (d, J=9.78 Hz, 1 H)7.54 (t, J=2.69 Hz, 1 H) 11.92 (br s, 1 H)

B.11. Synthesis of 6-bromo-7-chloro-1H-indole XI-11

To a solution of 1-bromo-2-chloro-3-nitro-benzene (500 mg, 1.9 mmol) inTHF (6 mL) was added vinyl magnesium bromide (7.6 mL, 1M, 7.6 mmol)dropwise at -78° C. and the reaction mixture was stirred at -78° C. for3h. Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was quenched with saturated NH₄Cl (60mL) and extracted with EtOAc (3x50 mL). The organic layer was separated,dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crudeobtained was purified by column chromatography (silica, 100-200 mesh,2-5% EtOAc in hexanes) to afford 6-bromo-7-chloro-1H-indole XI-11 (0.15g) as an off-white solid.

Yield: 32%

Basic LCMS Method 2 (ES⁻): 228 (M−H)⁻, 95% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.59-6.60 (m, 1 H) 7.26 (t, J=2.4 Hz, 1 H)7.34 (d, J=8.4 Hz,1 H) 7.42 (d, J=8.4 Hz,1 H) 8.41 (brs, 1 H).

B.12. Synthesis of 7-chloro-6-methoxy-1H-indole XI-12

To a solution of 2-chloro-1-methoxy-3-nitro-benzene (500 mg, 2.67 mmol)in THF (10.0 mL) was added bromo(vinyl)magnesium (1.00 M, 8.00 mL, 8.00mmol) at -78° C. The reaction mixture was stirred at same temperaturefor 3h. Progress was monitored by TLC. The reaction mixture was quenchedwith the addition of a saturated NH4C1 solution (15 mL) and extractedwith ethyl acetate (3×30 mL). The organic layer was washed with a brinesolution (30 mL), separated and concentrated under reduced pressure.Thecrude compound was purified by column chromatography (silica gel,100-200 mesh, in 2% EtOAc in hexanes) to afford7-chloro-6-methoxy-1H-indole XI-12 (0.15 g) as a white solid.

Yield: 30%

¹H NMR (400 MHz, DMSO-d₆) δ 3.86 (s, 3 H) 6.44 (s, 1 H) 6.92 (d, J=8.80Hz, 1 H) 7.26 (s, 1 H) 7.45 (d, J=8.80 Hz, 1 H) 11.15 (br s, 1 H)

B.13. Synthesis of 7-chloro-6-fluoro-IH-indole XI-13

To a solution of 2-chloro-1-fluoro-3-nitro-benzene (4.00 g, 22.8 mmol)in anhydrous tetrahydrofuran (40.0m1) under inert atmosphere, cooled to-78° C. was slowly added vinylmagnesium bromide (1.00 M, 91.1 mL, 91.1mmol). The reaction mixture was stirred at -78° C. for 3h. The reactionwas monitored by TLC. On completion, the reaction mixture was quenchedby adding it to a cold saturated aqueous NH4C1 solution (80 mL). Theaqueous layer was extracted with ethyl acetate (50 mL x 2). The organiclayer was separated, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was purified bysilica gel (100-200 mesh) column chromatography with 5% ethyl acetate inn-hexane to afford 7-chloro-6-fluoro-1H-indole XI-13 (2.0 g) as a paleyellow solid.

Yield: 45%

¹H NMR (400 MHz, DMSO-d₆) δ 6.52-6.54 (m, 1 H) 7.00-7.07 (m, 1 H) 7.42(t, J=2.69

Hz, 1 H) 7.49-7.55 (m, 1 H) 11.60 (br s, 1 H).

B.14. Synthesis of 6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine XI-14

To a solution of 1H-pyrrolo[2,3-b]pyridine-6-carbaldehyde (196 mg, 1.26mmol) in dichloromethane (4 mL) was added, at 0° C., diethylaminosulfurtrifluoride (260 pL, 1.91 mmol). The reaction mixture was stirred 4h atroom temperature. Pour the reaction on a mixture of ice and NaHCO₃ andextract 3 times with DCM. Dry the organic phase on

Na₂SO₄ and concentrate the solvents to get 6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine XI-14 (96 mg) as a brown solid

Yield: 45%.

Basic LCMS Method 1 (ES⁺): 169 (M+H)⁺, 82% purity.

B.15. Synthesis of 6-chloro-7-(difluoromethoxy)-1H-indole XI-15

Step-1: Synthesis of tert-butyl(2-chloro-6-nitrophenoxy)dimethylsilaneXI-15a

To a solution of 2-chloro-6-nitro-phenol (4.00 g, 23.0 mmol) in DCM (40mL) was added imidazole (4.71 g, 69.1 mmol) and TBSCI (3.82 g, 25.4mmol). The reaction mixture was stirred at room temperature for 4h.Progress of the reaction was monitored by TLC. After completion, thereaction mixture was diluted with H₂O (100 mL) and extracted with DCM(2×120 mL). The organic layer was separated, washed with a saturatedNaHCO₃ solution (2×100 mL), dried over anhydrous Na₂SO₄ and concentratedunder vacuum to afford tert-butyl(2-chloro-6-nitrophenoxy)dimethylsilaneXI-15a (7.50 g crude) as a pale brown liquid.

This compound was used as such for the next reaction without furtherpurification.

¹H NMR (400 MHz, DMSO-d₆) δ 0.15 (s, 6H) 0.97 (s, 9H) 7.21 (t, J=8.40Hz, 1H) 7.81-7.89 (m, 2H).

Step-2: Synthesis of 7-((tert-butyldimethylsilyl)oxy)-6-chloro-1H-indoleXI-15b

To a solution of tert-butyl(2-chloro-6-nitrophenoxy)dimethylsilaneXI-15a (7.49 g, 26.0 mmol) in THF (60 mL) was added vinylmagnesiumbromide (1 M, 104 mL, 104 mmol) dropwise at -78° C. and the reaction wasstirred at same temperature for 3h. The reaction mixture was thenstirred at room temperature for 16h. Progress of the reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasquenched with saturated NH₄CI (150 mL) and extracted with EtOAc (3×120mL). The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude obtained was purified by flashchromatography (1.3% EtOAc in hexanes) to afford7-((tert-butyldimethylsilyl)oxy)-6-chloro-1 H-indole XI-15b (2.00 g) asa pale yellow liquid.

Yield: 21%.

Basic LCMS Method 2 (ES⁻): 280 (M−H)⁻, 77% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 0.21 (s, 6H) 1.05 (s, 9H) 6.43 (dd, J=2.93,1.96 Hz, 1H) 6.96 (d, J=8.31 Hz, 1H) 7.17 (d, J=8.31 Hz, 1H) 7.30 (t,J=2.69 Hz, 1H) 10.60 (brs, 1H).

Step-3: Synthesis of 6-chloro-1-(phenylsulfonyl)-1H-indol-7-ol XI-15c

To a solution of 7-((tert-butyldimethylsilyl)oxy)-6-chloro-1H-indoleXI-15b (1.69 g, 4.60 mmol) in DMF (40 mL) was added NaH (0.92 g, 23.0mmol) portion wise at 0° C. and the reaction was stirred at sametemperature for 30 min. PhSO2Cl (0.98 g, 5.53 mmol) was added and thereaction mixture was stirred at room temperature for 8h. Progress of thereaction was monitored by TLC and LCMS. After completion, the reactionmixture was slowly poured into ice-cold H₂O (100 mL) and extracted withEtOAc (2×80 mL). The organic layer was separated, washed with H₂O (2×70mL), dried over anhydrous Na₂SO₄ and concentrated under vacuum. Thecrude obtained was purified by column chromatography (silica, 100-200mesh, 5 to 8% EtOAc in hexanes) to afford6-chloro-1-(phenylsulfonyl)-1H-indol-7-ol XI-15c (0.71 g) as anoff-white solid.

Yield: 41%.

Basic LCMS Method 2 (ES⁻): 306 (M−H)⁻, 81% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.77 (d, J=3.2 Hz, 1H) 7.07 (d, J=8.4 Hz,1H) 7.16 (d, J=8.4 Hz, 1H) 7.55-7.60 (m, 2H) 7.65-7.70 (m, 1H) 7.82 (d,J=3.2 Hz, 1 H) 7.85-7.88 (m, 2H) 9.70 (brs, 1 H).

Step-4: Synthesis of 6-chloro-7-(difluoromethoxy)-1-(phenylsulfonyl)-1H-indole XI-15d

To a solution of 6-chloro-1-(phenylsulfonyl)-1H-indol-7-ol XI-15c (0.70g, 1.85 mmol) in CH3CN (20 mL) was added KOH (0.52 g, 9.23 mmol)solution in H₂O (4 mL) at 0° C. and stirred at same temperature for 15min. Bromodifluoromethyl diethylphosphonate (1.64 mL, 9.23 mmol) wasadded dropwise at 0° C. and the reaction mixture was stirred at roomtemperature for 16h. Progress of the reaction was monitored by TLC.After completion, the reaction mixture was diluted with H₂O (60 mL) andextracted with EtOAc (2×50 mL). The organic layer was separated, driedover anhydrous Na₂SO₄ and concentrated under vacuum. The crude obtainedwas purified by flash chromatography (2 to 6% EtOAc in hexanes) toafford 6-chloro-7-(difluoromethoxy)-1-(phenylsulfonyI)-1H-indole XI-15d(0.41 g) as an off-white solid.

Yield: 53%.

Basic LCMS Method 2 (ES⁻): 356 (M−H)⁻, 86% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.97(d, J=4.0 Hz, 1H) 7.19 (t, J =74 Hz, 1H)7.42 (d,

J=8.0 Hz, 1H) 7.54-7.61 (m, 3H), 7.69 (t, J=7.2 Hz, 1 H) 7.77-7.80 (m,2H) 7.94(d, J=3.2 Hz, 1H).

Step-5: Synthesis of 6-chloro-7-(difluoromethoxy)-1H-indole XI-15

To a solution of6-chloro-7-(difluoromethoxy)-1-(phenylsulfonyI)-1H-indole XI-15d (0.41g, 0.97 mmol) in MeOH (6 mL) was added a K2CO3 (0.27 g, 1.95 mmol)solution in H₂O (2 mL) and the reaction mixture was heated at 60° C. for16h. Progress of the reaction was monitored by TLC and LCMS. Thereaction mixture was concentrated under vacuum. The residue was dilutedwith H₂O (40 mL) and extracted with EtOAc (3×30 mL). The organic layerwas separated, dried over anhydrous Na₂SO₄ and concentrated undervacuum. The crude obtained was purified by flash chromatography (1 to 3%EtOAc in hexanes) to afford 6-chloro-7-(difluoromethoxy)-1H-indole XI-15(0.205 g, 91%) as an off-white solid.

Yield: 91%.

Basic LCMS Method 2 (ES⁻): 216 (M−H)⁻, 93% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.53-6.55 (m, 1H) 7.11 (d, J=8.00 Hz, 1H)7.17 (t, J=74 Hz, 1H) 7.42 (d, J=2.40 Hz, 1H) 7.51 (d, J=8.00 Hz, 1 H)11.52 (brs, 1H).

B.16. Synthesis of 6-chloro-7-(trifluoromethyl)-1H-indole XI-16

Step 1- Synthesis of(E)-N-(3-chloro-2-(trifluoromethyl)phenyI)-2-(hydroxyimino)acetamideXI-16a

To a stirred solution of chloral hydrate (2.54 g, 15.3 mmol) in H₂O (30mL) was added (0.87 g, 6.14 mmol) and3-chloro-2-(trifluoromethyl)aniline (2.00 g, 10.2 mmol) followed byaddition of NH₂OH.HCI (2.13 g, 30.7 mmol) at room temperature. Thereaction mixture was heated at 55° C. for 16h. Progress of reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasdiluted with H₂O (100 mL) and extracted with EtOAc (2×40 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude obtained was purified bycombi-flash chromatography (10 to 20% EtOAc in hexanes) to(E)-N-(3-chloro-2-(trifluoromethyl)phenyl)-2-(hydroxyimino)acetamideXI-16a (1.25 g) as an off-white solid.

Yield: 44%.

Basic LCMS Method 2 (ES⁻): 265 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.48 (d, J=7.82 Hz, 1H) 7.61 (s, 1H)7.62-7.68 (m, 2H) 10.10 (s, 1H) 12.36 (s, 1H).

Step 2- Synthesis of 6-chloro-7-(trifluoromethyl)indoline-2,3-dioneXI-16b

To a stirred solution of H2504 (25 mL) was added(E)-N-(3-chloro-2-(trifluoromethyl)phenyl)-2-(hydroxyimino)acetamideXI-16a (2.50 g, 8.92 mmol) portion wise at 70° C. and the reactionmixture was heated at 90° C. for 3h. Progress of reaction was monitoredby TLC and LCMS. After completion, reaction mixture was poured intocrushed ice (150 mL) and extracted with EtOAc (2×40 mL). The organiclayer was separated, dried over anhydrous Na₂SO₄ and concentrated undervacuum to afford 6-chloro-7-(trifluoromethyl)indoline-2,3-dione XI-16b(2.31 g crude) as a pale yellow solid.

This compound was used as such for the next reaction without furtherpurification. Basic LCMS Method 2 (ES⁻): 248 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d6) δ 7.34 (d, J=7.82 Hz, 1H) 7.72 (d, J=7.82 Hz,1H) 11.20 (brs, 1H).

Step 3- Synthesis of 6-chloro-7-(trifluoromethyl)-1 H-indole XI-16

To a stirred solution of 6-chloro-7-(trifluoromethyl)indoline-2,3-dioneXI-16b (0.90 g, 3.49 mmol) in THF (20 mL) was added BH₃.Me₂S (2 M, 5.23mL, 10.5 mmol) at 0° C. and the reaction mixture was stirred at roomtemperature for 16h. Progress of reaction was monitored by TLC and LCMS.After completion, the reaction mixture was quenched with 2N HCI (20 mL),diluted with H₂O (60 mL) and extracted with EtOAc (3×40 mL). The organiclayer was separated, dried over anhydrous Na₂SO₄ and concentrated undervacuum. The reaction was repeated on 0.90 g and the crude obtained from2 reactions was clubbed in DCM (50 mL) and purified by combi-flashchromatography (0 to 5% EtOAc in hexanes) to afford6-chloro-7-(trifluoromethyl)-1 H-indole XI-16 (0.844 g) as a pale yellowliquid.

Yield: 53%.

Basic LCMS Method 2 (ES⁻): 218 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.64-6.65 (m, 1H) 7.26 (d, J=8.37 Hz, 1H)7.48-7.50 (m, 1H) 7.85 (d, J=8.37 Hz, 1 H) 11.38 (brs, 1 H).

C. Synthesis of intermediates of Formula XII C.1. Method A. Synthesis of1H-pyrrolo[3,2-h]quinoline-3-sulfonic acid XII-1

Step-1: Synthesis of 1H-pyrrolo[3,2-h]quinoline-3-sulfonic acid XII-1a

To a solution of 1H-pyrrolo[3,2-H]quinoline (400 mg, 2.3 mmol) inpyridine (6 mL) at 0° C., was added pyridine-sulfur trioxide complex(1.2 g, 3.5 mmol). The reaction mixture was then heated at 120° C. understirring for 2h, cooled to room temperature and evaporated to dryness.The beige solid was dissolved in water and the aqueous phase washed withchloroform (3×). A precipitate formed on standing in the aqueousfraction and was filtered, rinsed with water and dried under vacuum at35° C. to afford 470 mg of 1H-pyrrolo[3,2-H]quinoline-3-sulfonic acidXII-1a as a beige solid.

Yield: 79%.

Basic LCMS Method 1 (ES⁺): 249 (M+H)⁺, 100% purity.

Step 2: Synthesis of 1 H-pyrrolo[3,2-h]quinoline-3-sulfonyl chlorideXII-1

To a solution of 1H-pyrrolo[3,2-h]quinoline-3-sulfonic acid XII-la (855mg, 3.44 mmol) in acetonitrile (8.5 mL), under Argon, cooled to 0° C.,was added dropwise phosphorus oxychloride (1.06 g, 6.88 mmol). Thereaction mixture was then heated to 70° C. under stirring overnight.After cooling to room temperature, ice water was carefully added undervigorous stirring. A solid precipitated and was filtered, rinsed withwater and dried under vacuum at 35° C., affording 284 mg of 1H-pyrrolo[3,2-h]quinoline-3-sulfonyl chloride XII-1 as a beige solid.

Yield: 27%.

Basic LCMS Method 1 (ES⁺): 275 (M+H)⁺, after quenching aliquot withethylamine prior to the analysis

The following intermediates may be synthesized according a methodanalogous to Method A. When commercially available, starting materialsare identified by their CAS Register Numbers.

TABLE 3 Conditions, Conditions, Time (Step- N° Indoles XI Time (Step-1)Yield (%) 2) Yield (%) XII- 169674-01-5 130° C., 48 h  91 (crude)ACN/sulfolane 1/1, 58 (crude) 2 70° C., 1h XII- 233-34-1 125° C., 5 h 64 (crude) 70° C., 1 h 60 (crude) 3 XII- 17422-33-2 Reflux, 16 h 100(crude) ACN/sulfolane 1/1, 62 4 70° C., 3 h XII- XI-1 Reflux, 16 h 100(crude) ACN/sulfolane 1/1, 25 5 80° C., 2 h XII- 52415-29-9 Reflux, 48 h76 ACN/sulfolane 1/1, crude 6 70° C., 1 h XII- 55052-27-2 Reflux, 2 h 81ACN/sulfolane 1/1, 68 7 70° C., 1 h XII- 120-72-9 Reflux, 2 h 84ACN/sulfolane 1/1, 65 8 70° C., 1 h XII- XI-3 Reflux, 2 h 87ACN/sulfolane 1/1, 53 9 70° C., 1 h XII- 129848-59-5 Reflux, 2 h 91ACN/sulfolane 1/1, 78 10 70° C., 1 h XII- 15903-94-3 Reflux, 2 h 95ACN/sulfolane 1/1, 88 11 70° C., 1 h XII- 199526-97-1 Reflux, 2 h 90ACN/sulfolane 1/1, 77 12 70° C., 1 h XII- 399-51-9 Reflux, 2 h 88ACN/sulfolane 1/1, 82 13 70° C., 1 h XII- 51417-51-7 Reflux, 2 h 93ACN/sulfolane 1/1, 85 14 70° C., 1 h XII- 32996-24-0 Reflux, 2 h 94ACN/sulfolane 1/1, 62 15 70° C., 1 h XII- ACN/sulfolane 1/1, 163420-02-8 Reflux, 2 h 92 70° C., 1 h 81 XII- 143468-13-7 Reflux, 2 h 86ACN/sulfolane 1/1, 85 17 70° C., 1 h XII- 13544-43-9 Reflux, 2 h crudeACN/sulfolane 1/1, 68 18 70° C., 1 h

5,6-difluoro-1H-indole-3-sulfonyl chloride XII-2

Basic LCMS Method 2 (ES⁻): 250 (M−H)⁻1H-benzo[g]indole-3-sulfonylchloride XII-3

Basic LCMS Method 1 (ES⁻): 246 (M−H)⁻6-chloro-1H-indole-3-sulfonylchloride XII-4

¹H NMR (400 MHz, DMSO-d6) δ 7.32 (dd, J=8.56, 1.22 Hz, 1H) 7.71 (s, 1H)8.03 (d, J=8.80 Hz, 1H) 8.45 (d, J=2.93 Hz, 1H) 12.38 (brs, 1H).

6-cyclopropyl-1H-indole-3-sulfonyl chloride XII-5

¹H NMR (400 MHz, DMSO-d₆) δ 0.71 (m, 2H) 0.92 (m, 2H) 1.96-2.01 (m, 1H)7.27 (brs, 1H) 7.31 (s, 1H) 7.60 (d, J=8.31 Hz, 1H) 7.69 (d, J=8.31 Hz,1H) 10.85 (brs, 1H).

6-bromo-1 H-indole-3-sulfonyl chloride XII-6

Not characterized.

6-chloro-1 H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride XII-7

¹H NMR (500 MHz, DMSO-d₆) δ: 11.88 (s, 1H), 8.09 (d, J=8.2 Hz, 1H), 7.51(s, 1H),7.17 (d, J=8.2 Hz, 1H).

1H-indole-3-sulfonyl chloride XII-8

Not characterized.

6-(2-methoxyethoxy)-1H-indole-3-sulfonyl chloride XII-9

Not characterized.

1,6,7,8-tetrahydrocyclopenta[g]indole-3-sulfonyl chloride XII-10

¹H NMR (600 MHz, Benzene-d6) 6:8.05 (d, J=8.2 Hz, 1H), 7.16 (s, 1H),7.02(d, J=8.1 Hz, 1H),6.43 (s, 1H),2.71 (t, J=7.4 Hz, 2H),2.38 (t, J=7.4 Hz,2H),1.82-1.85 (m, 2H).

6-benzyloxy-1 H-indole-3-sulfonyl chloride XII-11

Not characterized.

4,6-difluoro-1H-indole-3-sulfonyl chloride XII-12

¹H NMR (600 MHz, Benzene-d₆) 6: 7.54 (d, J=8.8 Hz, 1H), 7.04-6.88 (m,1H), 6.73 (s, 1H), 6.46 (s, 1H).

6-fluoro-1 H-indole-3-sulfonyl chloride XII-13

¹H NMR (600 MHz, Benzene-d6) 6: 7.85 (dd, J=8.9, 5.1 Hz, 1H), 6.87 (d,J=3.2 Hz, 1H), 6.77-6.78 (m, 1H), 6.37 (dd, J=8.8, 2.2 Hz, 1H),6.32-6.10 (m, 1H).

7-bromo-1 H-indole-3-sulfonyl chloride XII-14

¹H NMR (600 MHz, Benzene-d6) 6: 8.03 (dd, J=8.8, 5.3 Hz, 1H), 7.33 (d,J=2.9 Hz, 1H), 6.88-6.89 (m, 1H), 6.44 (dd, J=9.1, 2.3 Hz, 1H), 6.36 (s,1H).

6-isopropyl-1H-indole-3-sulfonyl chloride XII-15

¹H NMR (600 MHz, Benzene-d6) 6: 8.10 (d, J=8.3 Hz, 1H), 7.16 (s, 1H),6.98-6.97 (m, 1H), 6.62 (d, J=1.4 Hz, 1H), 6.50 (s, 1H), 2.75 (sept,J=6.9 Hz, 1H), 1.15 (d, J=6.9 Hz, 6H).

6-methyl-1H-indole-3-sulfonyl chloride XII-16

Not characterized.

6-bromo-1 H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride XII-17

¹H NMR (500 MHz, DMSO-d₆) δ:11.86 (s, 1H, NH), 8.09 (d, J=8.2 Hz, 1H),7.50 (s, 1H), 7.16 (d, J=8.2 Hz, 1H).

6-trifluoromethyl-1 H-indole-3-sulfonyl chloride XII-18

Not characterized.

C.2. Synthesis of 1-(benzenesulfonyl)-6-chloro-indole XII-19

Step-1: Synthesis of 1-(benzenesulfonyl)-6-chloro-indole XII-19a

A suspension of finely powdered sodium hydroxide (24.5 g, 613 mmol) indichloromethane (300 mL) was stirred in an ice bath and 6-chloroindole(30 g, 197 mmol) was added in one portion followed by tetrabutylammoniumhydrogen sulfate (1.75 g, 5.15 mmol). Then benzenesulfonyl chloride (2.2mL, 218 mmol) was added dropwise over 20 min and the reaction mixturewas stirred at 0° C. for 1h. The ice bath was then removed and themixture was stirred for a further 1 h at room temperature. When LC/MSshowed completion of reaction, the reaction mixture was filtered througha celite pad and the latter was washed with DCM, combined filtrate andwashings were evaporated to dryness. The product was triturated inether, filtered, washed with small amount of ether then hexane anddried, the filtrate was concentrated to give a second crop with a totalof 50.54 g of 1-(benzensesulfonyl)-6-chloro-indole XII-19a as lightbrown solid.

Yield: 88%.

¹H NMR (400 MHz, CDC1₃) δ 8.04 (dd, J=1.8, 0.9 Hz, 1H), 7.91 (t, J=1.4Hz, 1H), 7.89 (t, J=1.8 Hz, 1H), 7.67-7.54 (m, 2H), 7.53-7.48 (m, 2H),7.48-7.42 (m, 1H), 7.23 (dd, J =8.4, 1.9 Hz, 1H), 6.65 (dd, J=3.7, 0.9Hz, 1H).

Step-2: Synthesis of 1-(benzenesulfonyl)-6-chloro-indole-3-sulfonylchloride XII-19

A solution of 1-(benzenesulfonyl)-6-chloro-indole XII-19a (50 g, 171.4mmol) in acetonitrile (500 mL) was stirred in an ice bath andchlorosulfonic acid (100.8 g, 856.8 mmol) was added dropwise over 20 minand the reaction mixture was stirred for 5 days at room temperature. Itwas then slowly poured with stirring into ice-water (2.2L) for 20 min,filtered, washed several times with water and dried by suction to give63.77g of 1-(benzenesulfonyl)-6-chloro-indole-3-sulfonyl chloride XII-19as light brown solid.

Yield: 95%.

¹H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1 H), 8.07 (d, J=1.8 Hz, 1 H), 8.04(t, J=1.3 Hz, 1H), 8.02 (d, J=1.5 Hz, 1H), 7.91 (d, J=8.6 Hz, 1H),7.79-7.70 (m, 1H), 7.68-7.59 (m, 2H), 7.47 (dd, J=8.6, 1.8 Hz, 1H).

C.3. Synthesis of1-(benzenesulfonyl)-6-chloro-pyrrolo[2,3-b]pyridine-3-sulfonyl chlorideXII-20

Step-1: Synthesis of 1-(benzenesulfonyI)-6-chloro-pyrrolo[2,3-b]pyridineXII-20a

To a solution of 6-chloro-1H-pyrrolo[2,3-b]pyridine (1.37 g, 8.97 mmol)in DMF (100 mL), sodium hydride (60% in paraffin, 1 g, 41 mmol) wasadded. The solution was stirred for 30 min being allowed to warm up from0 ° C. to rt. Subsequently, benzenesulfonic acid chloride (1.5 mL, 11.8mmol) was added dropwise. The suspension was stirred 3 h at roomtemperature and hydrolyzed with ice water. The resulting solid wasfiltered off under reduced pressure, washed thoroughly with water (75mL) and finally with petroleum ether (15 mL). The resulting material wasdried at 60 ° C. and purified by column chromatography (eluent: puredichloromethane) yielding 856 mg of1-(benzenesulfonyl)-6-chloro-pyrrolo[2,3-b]pyridine XII-20a as abrownish solid.

Yield: 32%

Step-2: Synthesis of1-(benzenesulfonyI)-6-chloro-pyrrolo[2,3-b]pyridine-3-sulfonyl chlorideXII-20

The obtained 1-(benzenesulfonyl)-6-chloro-pyrrolo[2,3-b]pyridine XII-20a(150 mg, 0.51 mmol) was dissolved in acetonitrile (5 mL) and treatedwith chlorosulfonic acid (2 mL, 2.91 mmol) dropwise. The mixture wasrefluxed for 3 h, cooled to room temperature, hydrolyzed with ice water(50 mL) and neutralized with a saturated solution of sodium hydrogencarbonate. The crude product was extracted with dichloromethane (3times, 50 mL each). The combined organic extracts were dried over MgSO₄,filtered and concentrated. The resulting material was purified by columnchromatography (eluent: pure dichloromethane) yielding 163 mg of1-(benzenesulfonyl)-6-chloro-pyrrolo[2,3-b]pyridine-3-sulfonyl chlorideXII-20 as a yellowish solid.

Yield: 81″⁻Yo

¹H NMR (600 MHz, CDCl₃) 6: 8.48 (s, 1H), 8.32 (d, J=7.8 Hz, 2H), 8.18(d, J=8.3 Hz, 1H),7.71 (t, J=7.5 Hz, 1H), 7.60 (t, J=7.9 Hz, 2H), 7.41(d, J=8.4 Hz, 1H).

C.4. Synthesis of1-(benzenesulfonyl)-6-(cyclopropylmethoxy)indole-3-sulfonyl chlorideXII-21

Step-1: Synthesis of 1-(benzenesulfonyl)-6-methoxy-indole XII-21a

To a solution of 6-methoxyindole (2.5 g, 17 mmol) in DMF (50 mL), sodiumhydride (60% in paraffin, 1.7 g, 71 mmol) was added at 0 ° C. Thesuspension was stirred for 30 min then warmed up to room temperature.Subsequently, the solution was treated with benzenesulfonyl chloride(2.8 mL, 3,70 g, 22 mmol) dropwise under stirring. After stirring atroom temperature for 2.5 h, ice water was added to the reaction mixtureunder vigorous stirring. The resulting precipitate was filtered offunder reduced pressure, washed thoroughly with water (100 mL) andsubsequently with petroleum ether (10 mL). After drying at 60 ° C.,1-(benzenesulfonyl)-6-methoxy-indole XII-21a was obtained as a colorlesssolid (3.2 g).

Yield: 65%

¹H NMR (600 MHz, CDC1₃) 6: 7.87-7.81 (m, 2H), 7.53-7.48 (m, 2H),7.45-7.39 (m, 3H), 7.36 (d, J=8.5 Hz, 1H), 6.84 (dd, J=8.6/2.3 Hz, 1H),6.56 (dd, J=3.7/0.9 Hz, 1H), 3.85 (s, 3H).

Step-2: Synthesis of 1-(benzenesulfonyl)indol-6-ol XII-21b

To a solution of 1-(benzenesulfonyl)-6-methoxyindole XII-21a (1 g, 3.5mmol) in dichloromethane (30 mL), boron tribromide (2.18 g, 0.83 mL, 8.7mmol) was added at room temperature. After 30 min of stirring at roomtemperature no further starting material could be detected (TLC control,eluent: pure dichloromethane). The reaction mixture was hydrolyzed byaddition of a saturated NaHCO₃-solution (70 mL). Water (50 mL) was addedand the aqueous phase was extracted with dichloromethane (three times,75 mL each). The combined organic extracts were dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel 60 (eluent:dichloromethane) yielding 600 mg of 1-(benzenesulfonyl)indol-6-olXII-21b as a colorless solid.

Yield: 63%

¹H NMR (600 MHz, DMSO-d₆) δ 9.58 (s, 1 H, OH), 7.93-7.85 (m, 2H),7.74-7.65 (m, 1 H), 7.62-7.56 (m, 2H), 7.54 (d, J=3.7 Hz, 1 H),7.39-7.29 (m, 2H), 6.81-6.62 (m, 2H).

Step-3: Synthesis of 1-(benzenesulfonyl)-6-(cyclopropylmethoxy)indoleXII-21c

A mixture of 1-(benzenesulfonyl)indol-6-ol XII-21b (273 mg, 1.0 mmol),cyclopropylmethyl iodide (224 mg, 1.22 mmol) and potassium carbonate(276 mg, 2.0 mmol) in butanone was heated at 80 ° C. for 16 h.Subsequently, the solvent was removed under reduced pressure and theresidue was treated with water (50 mL) and ethyl acetate (50 mL). Theorganic phase was separated and the aqueous phase was extracted twicewith ethyl acetate (50 mL each). The combined organic extracts weredried over MgSO₄, filtered and evaporated. The residue was purified bycolumn chromatography on silica gel 60 (eluent: pure dichloromethane)resulting in 1-(benzenesulfonyl)-6-(cyclopropylmethoxy)indole XII-21c asa colorless solid (269 mg).

Yield: 82%

Step-4 and 5: Synthesis of1-(benzenesulfonyl)-6-(cyclopropylmethoxy)indole-3-sulfonyl chlorideXII-21

To a solution of 1-(benzenesulfonyl)-6-(cyclopropylmethoxy)indoleXII-21c (130 mg, 0.39 mmol) in dichloromethane (2 mL) was addedSO₃.DMF-complex (75 mg, 0.49 mmol). After stirring at room temperaturefor 1.5 h, thionyl chloride (0.04 mL, 66 mg, 0.55 mmol) was added. Afterstirring at room temperature for a further 20 h the solvent wasevaporated and the oily residue was purified by column chromatography onsilica gel 60 (eluent: pure dichloromethane) resulting in 160 mg of1-(benzenesulfonyl)-6-(cyclopropylmethoxy)indole-3-sulfonyl chlorideXII-21 as a colorless solid. The product was not further characterizedbut directly used for the next steps.

Yield: 95%

C.5. Synthesis of 1-(benzenesulfonyl)-6-methoxy-indole-3-sulfonylchloride XII-22

A solution of 1-(benzenesulfonyl)-6-methoxyindole XII-21a (500 mg, 1.74mmol) in dichloromethane (15 mL) was treated with SO3·DMF complex (1.2g, 7.8 mmol) and stirred at room temperature for 2 h (TLC control). Theexpected intermediate indolesulfonic acid was not isolated.Subsequently, thionyl chloride (1 mL, 14 mmol) was added and the mixturewas stirred for 16 h at room temperature. The mixture was hydrolyzedwith a saturated solution of NaHCO₃ (50 mL) and extracted withdichloromethane (3 times, 50 mL each). The combined organic extractswere dried over MgSO₄, filtered and concentrated by vacuum evaporation.The residue was purified by column chromatography (silica gel 60,eluent, dichloromethane/petroleum ether=1:1) leading to1-(benzenesulfonyl)-6-methoxy-indole-3-sulfonyl chloride XII-22 as acolorless solid (504 mg).

Yield: 75%

¹H NMR (600 MHz, CDCl₃) 6: 8.23 (s, 1 H), 8.00-7.93 (m, 2H), 7.80 (d,J=8.8 Hz, 1H), 7.70-7.63 (m, 1 H), 7.59-7.53 (m, 2H), 7.47 (d, J=2.2 Hz,1 H), 7.06 (dd, J=8.8, 2.2 Hz, 1H), 3.89 (s, 3H).

C.6. Synthesis of1-(benzenesulfonyI)-6-(tetrahydrofuran-2-ylmethoxy)indole-3-sulfonylchloride XII-23

Step-1: Synthesis of1-(benzenesulfonyl)-6-(tetrahydrofuran-2-ylmethoxy)indole XII-21a

A mixture of 1-(benzenesulfonypindo1-6-ol XII-21b (273 mg, 1.0 mmol),2-bromomethyltetrahydrofuran (330 mg, 2.0 mmol) and K₂CO₃ (276 mg, 2.0mmol) in butanone was heated at 85 ° C. for 3 days. Subsequently, thesolvent was removed under reduced pressure and the residue treated withwater (50 mL) and ethyl acetate (50 mL). The organic phase was separatedand the aqueous phase was extracted twice with ethyl acetate (50 mLeach). The combined organic extracts were dried over MgSO4, filtered andevaporated. The residue was purified by column chromatography on silicagel 60 (eluent: pure dichloromethanType equation here.e) resulting in1-(benzenesulfonyl)-6-(tetrahydrofuran-2-ylmethoxy)indole XII-23a as acolorless solid (214 mg).

Yield: 60%

Step-2: Synthesis of1-(benzenesulfonyl)-6-(tetrahydrofuran-2-ylmethoxy)indole-3-sulfonylchloride XII-23

To a solution of1-(benzenesulfonyl)-6-(tetrahydrofuran-2-ylmethoxy)indole XII-23a (100mg, 0.28 mmol) in dichloromethane (2 mL) was added SO₃.DMF-complex (52mg, 0.34 mmol). After stirring at room temperature for 2 h, thionylchloride (0.1 mL, 81 mg, 1.4 mmol) was added. After stirring at roomtemperature for a further 16 h the solvent was evaporated and the oilyresidue was purified by column chromatography on silica gel 60 (eluent:pure dichloromethane) resulting in 64 mg of1-(benzenesulfonyl)-6-(tetrahydrofuran-2-ylmethoxy)indole-3-sulfonylchloride XII-23 as a colorless solid. The product was not furthercharacterized but directly used for the next steps.

Yield: 50%

C.7. Synthesis of 6-chlorobenzofuran-3-sulfonyl chloride XII-24

To a solution of SO₃-DMF (0.78 g, 4.90 mmol) in 1,2-dichloroethane (10mL) was added 6-chlorobenzofuran XI-2 (0.50 g, 3.27 mmol) and thereaction mixture was heated at 70° C. for 16h. The reaction mixture wascooled to 0° C. followed by addition of SOCl2 (0.52 mL, 7.16 mmol). Thereaction mixture was heated at 80° C. for 2h. Progress of the reactionwas monitored by TLC. After completion, the reaction mixture wasconcentrated under vacuum to afford 6-chlorobenzofuran-3-sulfonylchloride XII-24 (0.48 g) as a red semi-solid. The product was confirmedby TLC analysis only.

Yield: 60%

C.8. Synthesis of 6-chloro-7-methoxy-1H-indole-3-sulfonyl chlorideXII-25

To a solution of 6-chloro-7-methoxy-1 H-indole XI-4 (0.10 g, 0.55 mmol)in DCE (5 mL) was added S03-DMF (0.12 g, 0.82 mmol) and the reactionmixture was stirred at room temperature for 1 h. Progress of thereaction was monitored by TLC. After completion, the reaction mixturewas quenched with H₂O (15 mL) and washed with DCM (2×10 mL). The aqueouslayer was concentrated under vacuum. The crude obtained was dissolved inDCE (5 mL) followed by addition of oxalyl chloride (0.23 mL, 2.76 mmol)at 0° C. The reaction mixture was stirred at 0° C. for 10 min and atroom temperature for 5h. The reaction mixture was concentrated undervacuum to afford 6-chloro-7-methoxy-1H-indole-3-sulfonyl chloride XII-25(0.31 g crude) as brown oil.

This compound was used as such for the next reaction without furtherpurification.

¹H NMR (400 MHz, DMSO-d₆) δ 3.88 (s, 3H) 7.02 (d, J=8.80 Hz, 1 H) 7.33(d, J=2.40 Hz, 1H) 7.48 (d, J=8.80 Hz, 1 H) 7.95 (s, 1 H).

C.9. Synthesis of 6-chloro-7-fluoro-IH-indole-3-sulfonyl chloride XII-26

To a solution of 6-chloro-7-fluoro-1H-indole XI-5 (0.2 g, 0.78 mmol) inCH₃CN (5 mL) was added CISO₃H (1 mL) at 0° C. and the reaction mixturewas stirred at room temperature for 12h. Progress of the reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasdiluted with H₂O (100 mL) and extracted with EtOAc (2×150 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum to afford6-chloro-7-fluoro-1H-indole-3-sulfonyl chloride XII-26 (0.2 g) as abrown semi solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 87%

Basic LCMS Method 2 (ES⁺): 248.00 (M+H)⁺(corresponding sulfonic acid),89% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.08-7.12 (m, 1H) 7.41-7.44 (m, 1H) 7.53 (d,J=8.31 Hz, 1H) 11.83 (brs,1H).

C.10. Synthesis of6-(trifluoromethyl)-1H-pyrrolo[2,3-1]pyridine-3-sulfonyl chloride XII-27

To 6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine XI-6 (0.45 g, 2.16mmol) was added CISO₃H (4.50 mL) dropwise at 0° C. and the reactionmixture was stirred at same temperature for 10 min. The reaction mixturewas then stirred at room temperature for 2h.

Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was poured in to ice and extracted withEtOAc (60 mL). The organic layer was separated, dried over anhydrousNa₂SO₄ and concentrated under vacuum to afford6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride XII-27(0.41 g) as a brown semi solid.

This compound was used as such for the next reaction without furtherpurification. Yield: 58%

Basic LCMS Method 2 (ES⁺): 285 (M+H)⁺, 83% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.56 (d, J=7.83 Hz, 1H) 7.71 (s, 1H) 8.29(d, J=8.31 Hz, 1H) 12.12 (brs, 1H).

C.11. Synthesis of 5-bromo-6-chloro-1H-indole-3-sulfonyl chloride XII-28

To a solution of 5-bromo-6-chloro-1H-indole (2.00 g, 8.68 mmol) in CH3CN(50 mL) was added CISO3H (10.1 g, 86.8 mmol) at 0° C. and the reactionmixture was stirred at room temperature for 1 h. Progress of thereaction was monitored by TLC. After completion, the reaction mixturewas diluted with ice H₂O (100 mL) and extracted with EtOAc (2 x 50 mL).The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum to afford 5-bromo-6-chloro-1H-indole-3-sulfonyl chloride XII-28 (2.50 g) as an off-white solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 88%

¹H NMR (400 MHz, DMSO-d₆) δ 7.91 (s, 1H) 8.44 (s, 1H) 8.49 (d, J=2.80Hz, 1H) 12.89 (brs, 1H).

C.12. Synthesis of 7-bromo-6-chloro-1H-indole-3-sulfonyl chloride XII-29

To a solution of 7-bromo-6-chloro-1 H-indole XI-7 (1.50 g, 6.26 mmol) inCH₃CN (30 mL) was added CISO₃H (2 mL) at 0° C. and the reaction mixturewas stirred at same temperature for 15 min. The reaction mixture wasthen stirred at room temperature for 1 h. Progress of the reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasdiluted with EtOAc (50 mL) and H₂O (100 mL) and aqueous layer wasextracted with EtOAc (300 mL). The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated under vacuum. The crude obtained waspurified by washing with pentane (10 mL) to afford7-bromo-6-chloro-1H-indole-3-sulfonyl chloride XII-29 (1.40 g) as anoff-white solid.

Yield: 67%

Basic LCMS Method 2 (ES⁻): 308.00 (M−H)⁻(corresponding sulfonic acid),98% purity. ¹H NMR (400 MHz, DMSO-d₆) δ 7.23 (d, J=8.80 Hz, 1H) 7.39 (d,J=2.93 Hz, 1H) 7.73 (d, J=8.31 Hz, 1H) 11.46 (brs, 1H).

C.13. Synthesis of 6-bromo-4-fluoro-IH-indole-3-sulfonyl chloride XII-30

To a solution of 6-bromo-4-fluoro-1H-indole (0.25 g, 1.17 mmol) in CH₃CN(5 mL) was added CISO₃H (0.40 mL) at 0° C. and the reaction mixture wasstirred at same temperature for 1h. Progress of the reaction wasmonitored by TLC and LCMS. Reaction was repeated on 0.25 g scale and thecrude mixture of 2 reactions was clubbed. After completion, the reactionmixture was quenched with ice H₂O (100 mL) and extracted with EtOAc (300mL). The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum to afford6-bromo-4-fluoro-1H-indole-3-sulfonyl chloride XII-30 (0.255 g) as anoff-white solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 22%

Basic LCMS Method 2 (ES⁺): 294.00 (M+H)⁺(corresponding sulfonic acid),62% purity.

C.14. Synthesis of 6-chloro-5-fluoro-1H-indole-3-sulfonyl chlorideXII-31

To a solution of 6-chloro-5-fluoro-1H-indole (0.50 g, 2.95 mmol) inCH₃CN (5 mL) was added CISO₃H (0.5 mL) at 0° C. and the reaction mixturewas stirred at room temperature for 2h. Progress of the reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasquenched with ice H₂O (20 mL), filtered, washed with H₂O (25 mL) anddried under vacuum to afford 6-chloro-5-fluoro-1H-indole-3-sulfonylchloride XII-31 (0.33 g) as pale brown solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 42%

¹H NMR (400 MHz, DMSO-d₆) δ 7.49 (d, J=2.45 Hz, 1H) 7.52-7.57 (m, 2H)11.33 (brs, 1H).

C.15. Synthesis of 6-chloro-7-(2,2-difluoroethoxy)-1H-indole-3-sulfonylchloride XII-32

To a solution of 6-chloro-7-(2,2-difluoroethoxy)-1H-indole XI-8 (0.07 g,0.30 mmol) in CH₃CN (3 mL) was added CISO3H (0.30 mL) at 0° C. and thereaction mixture was stirred at room temperature for 2h. Progress of thereaction was monitored by TLC and LCMS. After completion, the reactionmixture was poured in to ice-cold H₂O (20 mL) and extracted with EtOAc(15 mL). The organic layer was separated, dried over anhydrous Na₂SO₄and concentrated under vacuum to afford6-chloro-7-(2,2-difluoroethoxy)-1 H-indole-3-sulfonyl chloride XII-32(0.09 g) as pale brown semi solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 90%

¹H NMR (400 MHz, DMSO-d₆) δ 4.31-4.46 (m, 2 H) 6.30-6.57 (m, 1 H)7.03-7.05 (d, J=8.8 Hz, 1 H) 7.38 (s, 1 H) 7.78-7.80 (d, J=8.0 Hz,1 H)11.38 (br s, 1 H).

C.16. Synthesis of5-(benzenesulfonyl)-[1,3]dioxolo[4,5-f]indole-7-sulfonyl chloride XII-33

Step-1: Synthesis of 5-(benzenesulfonyl)-[1,3]dioxolo[4,5-f]indoleXII-33a

A suspension of sodium hydroxide (0.3 g, 7.5 mmol) in dichloromethane (7mL) was stirred in an ice bath and 5H-[1,3]dioxolo[4,5-f]indole (0.5 g,3 mmol) was added followed by tetrabutylammonium hydrogen sulfate (0.3g, 0.08 mmol). Then benzenesulfonyl chloride (0.5 mL, 4 mmol) was addeddropwise. The ice bath was then removed and the mixture was stirred atroom temperature overnight. When LC/MS showed completion of reaction,the reaction mixture was poured into iced water and extracted with DCM(3 times), combined organic phases were dried over MgSO₄ and evaporatedto dryness. The product was purified by flash chromatography (elutingwith a a mixture of DCM and heptane) to provide 0.9 g of5-(benzenesulfonyl)-[1,3]dioxolo[4,5-f]indole XII-33a as a solid.

Yield: 100%.

Basic LCMS Method 1 (ES⁻): 300 (M−H)⁻, 100% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.98-7.58 (m, 6H), 7.44 (s, 1H), 7.07 (s,1H), 6.70 (s, 1H), 6.04 (s, 2H).

Step-2: Synthesis of5-(benzenesulfonyl)-[1,3]dioxolo[4,5-f]indole-7-sulfonyl chloride XII-33

A solution of 5-(benzenesulfonyl)-[1,3]dioxolo[4,5-f]indole XII-33a (0.4g, 1 mmol) in acetonitrile (4 mL) was stirred in an ice bath andchlorosulfonic acid (90 pL, 1.31 mmol) was added. The reaction mixturewas stirred overnight at room temperature. Next, phosphorous oxychloride(0.5 mL, 5 mmol) was added and the reaction mixture was heated at 70° C.overnight. It was then poured with stirring into ice-water, extractedtwice with chloroform, dried over MgSO₄ and evaporated to give 0.25g of5-(benzenesulfonyI)-[1,3]dioxolo[4,5-f]indole-7-sulfonyl chloride XII-33as a solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 62%.

Basic LCMS Method 1 (ES⁻): 398 (M−H)⁻, 100% purity.

C.17. Synthesis of 1-(benzenesulfonyI)-6-methoxy-pyrrolo[2,3-b]pyridine-3-sulfonyl chlorideXII-34

Step-1: Synthesis of1-(benzenesulfonyl)-6-methoxy-pyrrolo[2,3-b]pyridine XII-34a

A suspension of sodium hydroxide (0.3 g, 7.5 mmol) in dichloromethane (6mL) was stirred in an ice bath and 6-methoxy-1H-pyrrolo[2,3-b]pyridine(0.45 g, 3 mmol) was added followed by tetrabutylammonium hydrogensulfate (0.3 g, 0.08 mmol). Then benzenesulfonyl chloride (0.6 mL, 5mmol) was added dropwise. The ice bath was then removed and the mixturewas stirred at room temperature overnight. When LC/MS showed completionof reaction, the reaction mixture was poured into iced water andextracted with DCM (3 times), combined organic phases were dried overMgSO₄ and evaporated to dryness to provide 0.88 g of1-(benzenesulfonyI)-6-methoxy-pyrrolo[2,3-b]pyridine XII-34a as a solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 100%.

Basic LCMS Method 1 (ES⁺): 289 (M+H)⁺, 94% purity.

Step-2: Synthesis of1-(benzenesulfonyl)-6-methoxy-pyrrolo[2,3-b]pyridine-3-sulfonyl chlorideXII-34

A solution of 1-(benzenesulfonyl)-6-methoxy-pyrrolo[2,3-b]pyridineXII-34a (0.88 g, 3.1 mmol) in acetonitrile (3 mL) was stirred in an icebath and chlorosulfonic acid (1.5 mL, 22 mmol) was added. The reactionmixture was stirred overnight at 75° C. It was then poured with stirringinto ice-water, extracted twice with chloroform, dried over MgSO₄ andevaporated to give 0.5g of1-(benzenesulfonyl)-6-methoxy-pyrrolo[2,3-b]pyridine-3-sulfonyl chlorideXII-34 as a solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 40%.

Basic LCMS Method 1 (ES⁻): 394 (M−H)⁻, 95% purity.

C.18. Synthesis of 1-(benzenesulfonyl)-6-cyano-indole-3-sulfonylchloride XII-35

Step-1: Synthesis of 1-(benzenesulfonyl)-6-cyano-indole XII-35a

A suspension of sodium hydroxide (0.21 g, 5.25 mmol) in dichloromethane(6 mL) was stirred in an ice bath and 1 H-indole-6-carbonitrile (0.3 g,2 mmol) was added followed by tetrabutylammonium hydrogen sulfate (0.2g, 0.06 mmol). Then benzenesulfonyl chloride (0.33 mL, 2.6 mmol) wasadded dropwise. The ice bath was then removed and the mixture wasstirred at room temperature overnight. When LC/MS showed completion ofreaction, the reaction mixture was poured into iced water and extractedwith DCM (3 times), combined organic phases were dried over MgSO₄ andevaporated to dryness. The product was purified by flash chromatography(eluting with a mixture of DCM and heptane) to provide 0.58 g of1-(benzenesulfonyl)-6-cyano-indole XII-35a as a solid.

Yield: 100%.

Basic LCMS Method 1 (ES⁻): 281 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (s, 1 H), 8.14-8.11 (m, 3H), 7.84-7.61(m, 5H), 6.94 (s, 1H).

Step-2: Synthesis of 1-(benzenesulfonyl)-6-cyano-indole-3-sulfonylchloride XII-35

A solution of 1-(benzenesulfonyl)-6-cyano-indole XII-35a (0.3 g, 1 mmol)in acetonitrile (2 mL) was stirred in an ice bath and chlorosulfonicacid (140 pL, 2 mmol) was added. The reaction mixture was stirredovernight at room temperature. Next, phosphorous oxychloride (0.42 mL,4.5 mmol) was added and the reaction mixture was heated at 70° C.overnight. It was then poured with stirring into ice-water, extractedtwice with chloroform, dried over MgSO₄ and evaporated to give 0.42g of1-(benzenesulfonyl)-6-cyano-indole-3-sulfonyl chloride XII-35 as asolid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 100%.

Basic LCMS Method 1 (ES⁻): 379 (M−H)⁻, 100% purity.

C.19. Synthesis of1-(benzenesulfonyl)-6-bromo-pyrrolo[2,3-b]pyridine-3-sulfonyl chlorideXII-36

1C

Step-1: Synthesis of 1-(benzenesulfonyl)-6-bromo-pyrrolo[2,3-b]pyridineXII-36a

A suspension of finely powdered sodium hydroxide (6.3 g, 160 mmol) indichloromethane (100 mL) was stirred in an ice bath and6-bromo-pyrrolo[2,3-b]pyridine (10 g, 50.7 mmol) was added in oneportion followed by tetrabutylammonium hydrogen sulfate (0.45 g, 1.3mmol). Then benzenesulfonyl chloride (7.2 mL, 56 mmol) was addeddropwise over 10 min and the reaction mixture was stirred at 0° C. for2h. When LC/MS showed completion of reaction, the reaction mixture wasfiltered through a celite pad and the latter was washed with DCM,combined filtrate and washings were evaporated to dryness. The productwas triturated in ether, filtered, washed with small amount of etherthen hexane and dried, the filtrate was concentrated to give a secondcrop with a total of 16.8 g of1-(benzenesulfonyl)-6-bromo-pyrrolo[2,3-b]pyridine XII-36a as paleyellow solid.

Yield: 98%.

Basic LCMS Method 1 (ES⁻F): 337 (M+H)⁺, 90% purity.

¹H NMR (400 MHz, CDC1₃) δ 8.28 (t, J=1.4 Hz, 1 H), 8.25 (d, J=1.6 Hz,1H), 7.77-7.59 (m, 3H), 7.59-7.49 (m, 2H), 7.34 (d, J=8.2 Hz, 1 H), 6.57(d, J=4.0 Hz, 1H).

Step-2: Synthesis of1-(benzenesulfonyl)-6-bromo-pyrrolo[2,3-b]pyridine-3-sulfonyl chlorideXII-36

A solution of 1-(benzenesulfonyl)-6-bromo-pyrrolo[2,3-b]pyridine XII-36a(5 g, 14.8 mmol) in acetonitrile (50 mL) was stirred in an ice bath andchlorosulfonic acid (1.5 mL, 22 mmol) was added dropwise over 10 min.The reaction mixture was stirred for 1 h allowing the temperature torise slowly, then it was stirred at 60° C. overnight. It was then pouredwith stirring into ice-water, stirred for 20 min, extracted twice withethyl acetate. The extract was washed with water, a saturated solutionof sodium bicarbonate, dried over MgSO₄ and evaporated to give 4.23 g of1-(benzenesulfonyI)-6-bromo-pyrrolo[2,3-b]pyridine-3-sulfonyl chlorideXII-36 as an off-white solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 65%.

¹H NMR (400 MHz, CDCl₃) δ 8.51 (s, 1H), 8.38 (q, J=1.8 Hz, 1H), 8.35 (t,J=1.7 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.81-7.72 (m, 1H), 7.70-7.62 (m,2H), 7.60 (d, J=8.4 Hz, 1H).

C.20. Synthesis of1-(benzenesulfonyl)-6-(2,2,2-trifluoroethoxy)indole-3-sulfonyl chlorideXII-37

Step-1: Synthesis of 1-(benzenesulfonyI)-6-(2,2,2-trifluoroethoxy)indoleXII-37a:

The indole XII-21b (500 mg, 1.8 mmol) and cesium carbonate (1.19 g, 3.6mmol) were placed in 7 mL of DMF. Then 2,2,2-trifluoroethyltrifluoromethanesulfonate (637 mg, 2.7 mmol) was added and the reactionmixture was stirred 1 h at room temperature. Then water was added toprecipitate the product which was filtrated to afford1-(benzenesulfonyl)-6-(2,2,2-trifluoroethoxy)indole XII-37a as acolorless solid (630 mg).

Yield: 97%

¹H NMR (600 MHz, CDCl₃) δ 7.84 (d, J=7.6 Hz, 2H), 7.63-7.51 (m, 2H),7.50-7.39 (m, 4H), 6.93-6.88 (m, 1H), 6.59 (d, J=3.8 Hz, 1 H), 4.40 (q,J=8.0 Hz, 2H).

Step-2: Synthesis of1-(benzenesulfonyI)-6-(2,2,2-trifluoroethoxy)indole-3-sulfonyl chlorideXII-37

A solution of 1-(benzenesulfonyI)-6-(2,2,2-trifluoroethoxy)indoleXII-37a (600 mg, 1.689 mmol) in dichloromethane (10 mL) was treated withSO3·DMF complex (517 mg; 3.377 mmol) and stirred at room temperature for6 h until all starting material was consumed (TLC control).Subsequently, thionyl chloride (1 mL; 13.78 mmol) was added and themixture was stirred overnight at room temperature. The resulting mixturewas quenched with saturated NaHCO₃ and extracted twice withdichloromethane. The organic phase were evaporated to dryness andpurified by column chromatography (silica gel 60, eluent,dichloromethane/petroleum ether =1:1) leading to1-(benzenesulfonyl)-6-(2,2,2-trifluoroethoxy)indole-3-sulfonyl chlorideXII-37 (306 mg) as a yellowish solid.

Yield: 40%

¹H NMR (600 MHz, CDC1₃) δ 8.28 (s, 1 H), 7.97 (d, J=8.0 Hz, 1 H), 7.86(d, J=8.8 Hz, 1H), 7.74-7.53 (m, 5H), 7.11 (dd, J=8.8, 2.2 Hz, 1H) 4.44(q, J=7.9 Hz, 2H).

C.21. Synthesis of 6-chlorobenzothiophene-3-sulfonyl chloride XII-38

To a solution of 6-chlorobenzothiophene XI-9 (0.30 g, 1.77 mmol) in DCM(15 mL) was added CISO3H (0.36 mL, 5.33 mmol) at 0° C. and the reactionmixture was stirred at same temperature for 5h. Progress of the reactionwas monitored by TLC. After completion, the reaction mixture wasquenched with ice-cold H₂O (50 mL) and extracted with EtOAc (2×50 mL).The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum to afford 6-chlorobenzothiophene-3-sulfonylchloride XII-38 (0.31 g) as an off-white solid.

Yield: 65%

¹H NMR (400 MHz, DMSO-d₆) δ 7.42-7.44 (m, 1H) 7.81 (s, 1H) 8.05-8.15 (m,2H).

C.22. Synthesis of 6-bromo-7-methyl-1H-indole-3-sulfonyl chloride XII-39

To a solution of 6-bromo-7-methyl-1 H-indole (0.12 g, 0.55 mmol) in ACN(1.8 mL) was added CISO₃H (0.15 mL, 2.21 mmol) at 0° C. and the reactionmixture was stirred at room temperature for 2h. After completion, thereaction mixture was quenched with H₂O and extracted with CHCI₃ (3 x).The organic layers were separated, dried over anhydrous MgSO₄ andconcentrated under vacuum to afford6-bromo-7-methyl-1H-indole-3-sulfonyl chloride XII-39 (0.11 g) as abeige solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 63%

Basic LCMS Method 1 (ES⁻): 315 (M−H)⁻, after quenching aliquot withethylamine prior to the analysis

C.23. Synthesis of 6-nitro-1H-indole-3-sulfonyl chloride XII-40

To a solution of 6-nitro-1 H-indole (2 g, 12.3 mmol) in CH3CN (30 mL)was added CISO₃H (4 mL) at 0° C. and the reaction mixture was stirred atroom temperature for 2h. Progress of the reaction was monitored by TLC.After completion, the reaction mixture was quenched with ice-cold H₂O(150 mL), filtered and washed with H₂O (10 mL). The crude obtained wasdried under vacuum to afford 6-nitro-1 H-indole-3-sulfonyl chlorideXII-40 (2.10 g) as a pale yellow solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 64%

¹H NMR (400 MHz, DMSO-d₆) δ 7.78 (s, 1 H) 7.92 (brs, 2H) 8.31 (s, 1H)11.82 (brs, 1H).

C.24. Synthesis of 6-chloro-5,7-difluoro-1H-indole-3-sulfonyl chlorideXII-41

To a solution of 6-chloro-5,7-difluoro-1H-indole XI-10 (700 mg, 3.6mmol) in CH₃CN (15 mL) was added CISO₃H (0.8 mL) at 0° C. and thereaction mixture was stirred at room temperature for 2h. Progress of thereaction was monitored by TLC and LCMS. After completion, the reactionmixture was diluted with water (50 mL) and extracted with EtOAc (100mL). The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum to afford 6-chloro-5,7-difluoro-1H-indole-3-sulfonyl chloride XII-41 (705 mg) as a brown solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 64%

Basic LCMS Method 2 (ES⁻): 266 (M−H)⁻(corresponding sulfonic acid), 93%purity.

C.25. Synthesis of 6-bromo-7-chloro-1H-indole-3-sulfonyl chloride XII-42

To a solution of 6-bromo-7-chloro-1H-indole XI-11 (145 mg, 0.6 mmol) inCH₃CN (3 mL) was added CISO3H (0.15 mL) at 0° C. and the reactionmixture was stirred at room temperature for 3h. Progress of the reactionwas monitored by TLC and LCMS. After completion, the reaction mixturewas poured on crushed ice (20 mL) and the formed solid was filtered anddried to afford 6-bromo-7-chloro-1H-indole-3-sulfonyl chloride XII-42(90 mg) as a pale brown solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 44%

Basic LCMS Method 2 (ES⁻): 308 (M−H)⁻(corresponding sulfonic acid), 95%purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.32-7.37 (m, 2H) 7.64 (d, J=8.8 Hz,1 H)11.58 (s, 1 H).

C.26. Synthesis of 7-chloro-6-methoxy-1H-indole-3-sulfonyl chlorideXII-43

To a solution of 7-chloro-6-methoxy-1 H-indole XI-12 (600 mg, 3.22 mmol)in acetonitrile (15 mL). Chlorosulfonic acid (0.6 mL) was added dropwiseat -5 to 0° C. The reaction mixture was stirred at room temperature for3 h. Progress of reaction was monitored by TLC. The reaction mixture waspoured on ice water (15 mL) extracted with EtOAc (3×15 mL). Combinedorganic layers were washed with a brine solution (15 mL), The organiclayer was separated, dried over anhydrous Na₂SO₄ (1.00 g) andconcentrated under vacuum. The crude compound was triturated withn-pentane (15 mL) to afford 7-chloro-6-methoxy-1H-indole-3-sulfonylchloride XII-43 (530 mg) as an off-white solid.

Yield: 58%

¹H NMR (400 MHz, DMSO-d₆) δ 3.86 (s, 3H) 6.97 (d, J=8.80 Hz, 1 H) 7.27(d, J=2.45 Hz, 1 H) 7.63 (d, J=8.31 Hz, 1 H) 11.19 (br s, 1 H)

C.27. Synthesis of 7-chloro-6-fluoro-IH-indole-3-sulfonyl chloride XII-4

To a solution of 7-chloro-6-fluoro-1H-indole XI-13 (400 mg, 2.08 mmol)in acetonitrile (8 mL) at 0° C. was slowly added CISO3H (0.345 mL, 5.19mmol). The reaction mixture was stirred at 0° C. for 1 h and then atroom temperature for 2h. Progress of the reaction was monitored by TLC.After completion, the reaction mixture was poured into ice water (50mL). The aqueous layer was extracted with ethyl acetate (2 x 25 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄, filtered andconcentrated to afford 7-chloro-6-fluoro-1 H-indole-3-sulfonyl chlorideXII-44 (430 mg) as a brown semi solid.

The crude product was used for next reaction without furtherpurification.

Yield: 62%

¹H NMR (400 MHz, DMSO-d₆) δ 7.07 (t, J=9.29 Hz, 1 H) 7.38 (d, J=2.45 Hz,1 H) 7.67-7.70 (m, 1 H) 11.60 (br s, 1 H).

C.28. Synthesis of1-(benzenesulfonyI)-6-(difluoromethyl)pyrrolo[2,3-b]pyridine-3-sulfonylchloride XII-45

Step-1: Synthesis of1-(benzenesulfonyl)-6-(difluoromethyppyrrolo[2,3-b]pyridine XII-45a

A suspension of sodium hydroxide (76 mg, 1.88 mmol) in dichloromethane(1 mL) was stirred in an ice bath and 6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine XI-14 (125 mg, 0.74 mmol) was added followed bytetrabutylammonium hydrogen sulfate (7.5 g, 0.022 mmol). Thenbenzenesulfonyl chloride (105 pL, 0.81 mmol) was added dropwise and thereaction mixture was stirred at room temperature overnight. Aftercompletion of reaction, the mixture was filtered through a celite padand the latter was washed with DCM, combined filtrate and washings wereevaporated to dryness. The crude product was purified by chromatography(Si0₂, elution with dichloromethane) to afford1-(benzenesulfonyl)-6-(difluoromethyl)pyrrolo[2,3-b]pyridine XII-45a(200mg) as a light brown solid.

Yield: 70%.

Basic LCMS Method 1 (ES⁺): 309 (M+H)⁺, 100% purity.

Step-2: Synthesis of1-(benzenesulfonyl)-6-(difluoromethyppyrrolo[2,3-b]pyridine-3-sulfonylchloride XII-45

A solution of1-(benzenesulfonyl)-6-(difluoromethyppyrrolo[2,3-b]pyridine XII-45a (76mg, 0.24 mmol) in acetonitrile (10 mL) was stirred in an ice bath andchlorosulfonic acid (54 μL, 0.78 mmol) was added dropwise and thereaction mixture was stirred for 4 days at 50° C. Then, phosphorousoxychloride (100 pL, 1.06 mmol) was added and the reaction mixture washeated at 70° C. overnight. After cooling, it was then slowly pouredinto ice-water and extracted with chloroform (3x). The organic layerswere dried over magnesium sulfate and evaporated to dryness to give1-(benzenesulfonyl)-6-chloro-indole-3-sulfonyl chloride XII-19 (100 mg)as a solid.

The crude product was used for next reaction without furtherpurification.

Yield: 95%.

Basic LCMS Method 1 (ES⁻): 387 (M−H)⁻ (corresponding sulfonic acidmass), 88% purity.

C.29. Synthesis of 6-chloro-7-(difluoromethoxy)-1H-indole-3-sulfonylchloride XII-46

To a solution 6-chloro-7-(difluoromethoxy)-1 H-indole XI-15 (0.20 g,0.86 mmol) in CH₃CN (4 mL) was added CISO₃H (0.20 mL) slowly at 0° C.and the reaction mixture was stirred at room temperature for 3h.Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was poured into crushed ice (20 mL) andextracted with EtOAc (3×10 mL). The organic layer was separated, driedover anhydrous Na₂SO₄ and concentrated under vacuum to afford6-chloro-7-(difluoromethoxy)-1 H-indole-3-sulfonyl chloride XII-46 (0.23g, crude) as a pale brown solid.

This compound was used as such for the next reaction without furtherpurification.

Basic LCMS Method 2 (ES⁻): 314 (M−H)⁻, 55% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.16 (d, J=8.80 Hz, 1H) 7.16 (t, J=73.6 Hz,1H) 7.39 (d, J=2.40 Hz, 1 H) 7.67 (d, J=8.80 Hz, 1H) 11.53 (brs, 1 H)

C.30. Synthesis of 6-chloro-7-(trifluoromethyl)-1H-indole-3-sulfonylchloride XII-47

To a stirred solution of 6-chloro-7-(trifluoromethyl)-1H-indole XI-16(0.52 g, 2.30 mmol) in CH₃CN (10 mL) was added CISO₃H (1.50 mL) dropwiseat 0° C. The reaction mixture was stirred at room temperature for 2h.Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was poured into crushed ice (100 mL),stirred for 10 min and extracted with EtOAc (3×40 mL). The organic layerwas separated, dried over anhydrous Na₂SO₄ and concentrated under vacuumto afford 6-chloro-7-(trifluoromethyl)-1 H-indole-3-sulfonyl chlorideXII-47 (1.01 g crude) as a brown solid.

This compound was used as such for next reaction without furtherpurification. Basic LCMS Method 2 (ES⁻): 298 (M−H)⁻(correspondingsulfonic acid mass), 96% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.31 (d, J=8.80 Hz, 1H) 7.41 (d, J=2.93 Hz,1H) 8.01 (d,

J=8.31 Hz, 1H) 11.27 (brs, 1H).

EXAMPLE COMPOUNDS D. Synthesis of compounds of general Formula I

All compounds of the present invention specifically disclosed herein aredesignated “1-x” wherein any “x” refers to a number identifying theindividual compounds. Accordingly, the Example compounds are designated1-1, 1-2, 1-3 etc. This is irrespective of whether any compound couldalso be described by any subgeneric Formula herein, e.g. by Formula II,III or IV, and the like.

D.1. Method B. Synthesis of6-chloro-N-(2,4-difluorophenyI)-1H-indole-3-sulfonamide 1-1

In a vial, a solution of 6-chloro-indole (630 mg, 4.1 mmol) inacetonitrile (25.2 mL) was stirred in an ice-bath and chlorosulfonicacid (714 μl, 10.7 mmol) was added dropwise and the reaction mixture wasstirred for 30 min. The ice-bath was removed and the reaction mixturewas heated to 60° C. for 1.5h. After cooling to room temperature,pyridine (54.6 mL) was added and the solution turned yellow. In a secondsealed vial, 2,4-difluoroaniline (25.8 mg, 0.2 mmol) was weighed and analiquot of the preceding solution was added (1.9 mL, 0.1 mmol). Thereaction mixture was stirred at 80° C. for 2h, then evaporated in ancentrifugal evaporator. The residue was purified by reverse phasechromatography in basic mode with MS detection to afford 11.8 mg of6-chloro-N-(2,4-difluorophenyI)-1H-indole-3-sulfonamide I-1.

Yield: 34%.

Basic LCMS Method 1 (ES⁻): 341 (M−H)⁻, 95% purity. The followingcompounds in table 4 were synthesized according to Method B.

TABLE 4 Basic Basic LCMS LCMS Method Method 1 1 (ES⁻): Indoles AminesYield (ES⁻ ⁾: purity No XI X Structure Name % (M − H)⁻ (%) I-2  3189-13-7 367-34- 0

6-methoxy-N-(2,4,5- trifluorophenyl)-1H-indole-3- sulfonamide  3.9 355100 I-3  17422- 33-2 533-30- 2

N-(1,3-benzothiazol-6-yl)-6- chloro-1H-indole-3- sulfonamide 29   362100 I-4  17422- 33-2 2106- 05-0

6-chloro-N-(5-chloro-2- fluorophenyl)-1H-indole-3- sulfonamide 23   357 93 I-5  17422- 33-2 14268- 66-7

N-(1,3-benzodioxol-5-yl)-6- chloro-1H-indole-3- sulfonamide 16   349  94I-6  17422- 33-2 619-45- 4

methyl 4-{[(6-chloro-1H- indol-3- yl)sulfonyl]amino}benzoate 16   363100 I-7  17422- 33-2 452-77- 7

6-chloro-N-(3-fluoro-4- methylphenyl)-1H-indole-3- sulfonamide 43   337100 I-8  17422- 33-2 57319- 65-0

6-chloro-N-(3-oxo-1,3- dihydro-2-benzofuran-5-yl)-1H-indole-3-sulfonamide 16   361 100 I-9  17422- 33-2 367-30- 6

6-chloro-N-(2,5- difluorophenyl)-1H-indole-3- sulfonamide 14   341 100I-10 17422- 33-2 20503- 39-3

6-chloro-N-(1,1-dioxido-2,3- dihydro-1-benzothiophen-6-yl)-1H-indole-3-sulfonamide 21   395  98 I-11 17422- 33-2 348-54- 9

6-chloro-N-(2-fluorophenyl)- 1H-indole-3-sulfonamide 22   323 100 I-1217422- 33-2 873-74- 5

6-chloro-N-(4-cyanophenyl)- 1H-indole-3-sulfonamide 15   330  98 I-1310075- 50-0 873-74- 5

5-bromo-N-(4-cyanophenyl)- 1H-indole-3-sulfonamide 32   374 100 I-14467461- 40-1 873-74- 5

N-(4-cyanophenyl)-6- (methylsulfonyl)-1H-indole-3- sulfonamide  7.5 374100 I-15 16066- 91-4 873-74- 5

N-(4-cyanophenyl)-5-iodo- 1H-indole-3-sulfonamide 29.5 422 100 I-1653924- 05-3 873-74- 5

7-chloro-N-(4-cyanophenyl)- 1H-indole-3-sulfonamide 35.5 330 100 I-1717422- 32-1 873-74- 5

5-chloro-N-(4-cyanophenyl)- 1H-indole-3-sulfonamide 23   330  98 I-18248602- 16-6 873-74- 5

6-bromo-N-(4-cyanophenyl)- 5-methyl-1H-indole-3- sulfonamide 20   388100 I-19 267-48-1 873-74- 5

N-(4-cyanophenyl)-5H- [1,3]dioxolo[4,5-f]indole-7- sulfonamide 20   340 96 I-20 3420-02- 8 106876- 54-4

N-(4-cyanophenyl)-6-methyl- 1H-indole-3-sulfonamide 20   310  95 I-2117422- 33-2 372-39- 4

6-chloro-N-(3,5- difluorophenyl)-1H-indole-3- sulfonamide 30   341 100I-22 17422- 33-2 14235- 81-5

6-chloro-N-(4-ethynylphenyl)- 1H-indole-3-sulfonamide 28.5 329  97 I-2317422- 33-2 21397- 08-0

6-chloro-N-(2-chloro-3- fluorophenyl)-1H-indole-3- sulfonamide 14   357 96 I-24 17422- 33-2 106-47- 8

6-chloro-N-(4-chlorophenyl)- 1H-indole-3-sulfonamide 8  339 100 I-2517422- 33-2 1668- 84-4

N-(1,3-benzodioxol-4-yl)-6- chloro-1H-indole-3- sulfonamide 32   349 100I-26 17422- 33-2 95-51-2

6-chloro-N-(2-chlorophenyl)- 1H-indole-3-sulfonamide 23   339  98 I-27248602- 16-6 367-30- 6

6-bromo-N-(2,5- difluorophenyl)-5-methyl-1H- indole-3-sulfonamide 43  399 100 I-28 467461- 40-1 367-30- 6

N-(2,5-difluorophenyl)-6- (methylsulfonyl)-1H-indole-3- sulfonamide 18.5385 100 I-29 3420-02- 8 1668- 84-4

N-(1,3-benzodioxol-4-yl)-6- methyl-1H-indole-3- sulfonamide 9  329  80I-30 267-48-1 367-30- 6

N-(2,5-difluorophenyl)-5H- [1,3]dioxolo[4,5-f]indole-7- sulfonamide 12  351 100 I-31 399-51-9 1668- 84-4

N-(1,3-benzodioxol-4-yl)-6- fluoro-1H-indole-3- sulfonamide 44   335 100I-32 3420-02- 8 367-30- 6

N-(2,5-difluorophenyl)-6- methyl-1H-indole-3- sulfonamide 7  321 100I-33 467461- 40-1 1668- 84-4

N-(1,3-benzodioxol-4-yl)-6- (methylsulfonyl)-1H-indole-3- sulfonamide39   393 100 I-34 467461- 40-1 14235- 81-5

N-(4-ethynylphenyl)-6- (methylsulfonyl)-1H-indole-3- sulfonamide 28.5373  90 I-35 248602- 16-6 1668- 84-4

N-(1,3-benzodioxol-4-yl)-6- bromo-5-methyl-1H-indole-3- sulfonamide 65.5407  97 I-36 467461- 40-1 1544- 85-0

N-(2,2-difluoro-1,3- benzodioxol-5-yl)-6- (methylsulfonyl)-1H-indole-3-sulfonamide 50   429 100 I-37 399-51-9 367-30- 6

N-(2,5-difluorophenyl)-6- fluoro-1H-indole-3- sulfonamide 34   325 100I-38 17422- 33-2 1003- 99-2

N-(2-bromo-5-fluorophenyl)- 6-chloro-1H-indole-3- sulfonamide 25.5 401 94 I-39 17422- 33-2 100-01- 6

6-chloro-N-(4-nitrophenyl)- 1H-indole-3-sulfonamide 15   350 100 I-4017422- 33-2 116632- 24-7

6-chloro-N-(4,6- dichloropyridin-2-yl)-1H- indole-3-sulfonamide 1  374100 I-41 399-51-9 367-34- 0

6-fluoro-N-(2,4,5- trifluorophenyl)-1H-indole-3- sulfonamide 38.5 343100 I-42 13544- 43-9 29632- 74-4

N-(2-fluoro-4-iodophenyl)-6- (trifluoromethyl)-1H-indole-3- sulfonamide34.5 483 100 I-43 267-48-1 57946- 56-2

N-(4-chloro-2-fluorophenyl)- 5H-[1,3]dioxolo[4,5-f]indole- 7-sulfonamide 5.8 367  93 I-44 267-48-1 29632- 74-4

N-(2-fluoro-4-iodophenyl)- 5H-[1,3]dioxolo[4,5-f]indole- 7-sulfonamide7  459  97 I-45 233-34-1 57946- 56-2

N-(4-chloro-2-fluorophenyl)- 1H-benzo[g]indole-3- sulfonamide  3.4 373100 I-46 267-48-1 367-34- 0

N-(2,4,5-trifluorophenyl)-5H- [1,3]dioxolo[4,5-f]indole-7- sulfonamide 9.5 369  94 I-47 233-34-1 29632- 74-4

N-(2-fluoro-4-iodophenyl)- 1H-benzo[g]indole-3- sulfonamide 3  465 100I-48 467461- 40-1 29632- 74-4

N-(2-fluoro-4-iodophenyl)-6- (methylsulfonyl)-1H-indole-3- sulfonamide29.4 493 100 I-49 399-51-9 29632- 74-4

6-fluoro-N-(2-fluoro-4- iodophenyl)-1H-indole-3- sulfonamide 47   433 98 I-50 467461- 40-1 57946- 56-2

N-(4-chloro-2-fluorophenyl)- 6-(methylsulfonyl)-1H-indole- 3-sulfonamide13   401 100 I-51 399-51-9 57946- 56-2

N-(4-chloro-2-fluorophenyl)- 6-fluoro-1H-indole-3- sulfonamide 50   341100 I-52 233-34-1 367-34- 0

N-(2,4,5-trifluorophenyl)-1H- benzo[g]indole-3-sulfonamide  3.4 375 100I-53 13544- 43-9 57946- 56-2

N-(4-chloro-2-fluorophenyl)- 6-(trifluoromethyl)-1H-indole-3-sulfonamide 41.9 391  97 I-54 13544- 43-9 367-34- 0

6-(trifluoromethyl)-N-(2,4,5- trifluorophenyl)-1H-indole-3- sulfonamide38.2 393  90 I-55 17422- 33-2 36556- 60-2

6-chloro-N-(2-chloro-3,5- difluorophenyl)-1H-indole-3- sulfonamide 2 375 100 I-56 17422- 33-2 452-80- 2

6-chloro-N-(2-fluoro-4- methylphenyl)-1H-indole-3- sulfonamide 41.6 337 97 I-57 17422- 33-2 45644- 21-1

6-chloro-N-(6-chloropyridin- 2-yl)-1H-indole-3-sulfonamide  7.6 340 100I-58 17422- 33-2 17920- 35-3

6-chloro-N-(6- methoxypyridin-2-yl)-1H- indole-3-sulfonamide 20.7 336100 I-59 17422- 33-2 695-34- 1

6-chloro-N-(3,5- dichloropyridin-2-yl)-1H- indole-3-sulfonamide  3.9 320100 I-60 17422- 33-2 662117- 63-7

6-chloro-N-(5-chloro-4- methoxypyridin-2-yl)-1H- indole-3-sulfonamide 0.4 370 100 I-61 17422- 33-2 42182- 27-4

6-chloro-N-(5-cyanopyridin-2- yl)-1H-indole-3-sulfonamide  0.6 331  98I-62 17422- 33-2 21717- 96-4

6-chloro-N-(5-fluoropyridin-2- yl)-1H-indole-3-sulfonamide 20.6 324 100I-63 17422- 33-2 1072- 98-6

6-chloro-N-(5-chloropyridin- 2-yl)-1H-indole-3-sulfonamide 11   340 100I-64 3189-13- 7 767-64- 6

N-(2,1,3-benzothiadiazol-4- yl)-6-methoxy-1H-indole-3- sulfonamide 1 359 100 I-65 233-88-5 57946- 56-2

N-(4-chloro-2-fluorophenyl)- 1H-pyrrolo[3,2-h]quinoline-3- sulfonamide10   374  88 I-66 233-88-5 106876- 54-4

N-(2,2-difluoro-1,3- benzodioxol-4-yl)-1H- pyrrolo[3,2-h]quinoline-3-sulfonamide  4.2 402 100 I-67 233-88-5 367-34- 0

N-(2,4,5-trifluorophenyl)-1H- pyrrolo[3,2-h]quinoline-3- sulfonamide 8.6 376  89 I-68 15861- 36-6 120934- 03-4

6-cyano-N-(2,2,6-trifluoro- 1,3-benzodioxol-5-yl)-1H-indole-3-sulfonamide 22.9 394 100 I-69 3189-13- 7 57946- 56-2

N-(4-chloro-2-fluorophenyl)- 6-methoxy-1H-indole-3- sulfonamide  2.3 353100 I-70 233-88-5 120934- 03-4

N-(2,2,6-trifluoro-1,3- benzodioxol-5-yl)-1H- pyrrolo[3,2-h]quinoline-3-sulfonamide  7.3 420 100 I-71 3189-13- 7 120934- 03-4

6-methoxy-N-(2,2,6-trifluoro- 1,3-benzodioxol-5-yl)-1H-indole-3-sulfonamide 3  399 100 I-72 3189-13- 7 106876- 54-4

N-(2,2-difluoro-1,3- benzodioxol-4-yl)-6-methoxy-1H-indole-3-sulfonamide  2.3 381 100 I-73 233-88-5 767-64- 6

N-(2,1,3-benzothiadiazol-4- yl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide  8.1 380  89 I-74 129848- 59-5 767-64- 6

N-(2,1,3-benzothiadiazol-4- yl)-1,6,7,8- tetrahydrocyclopenta[g]indole-3-sulfonamide  2.9 369  82 I-75 15861- 36-6 367-34- 0

6-cyano-N-(2,4,5- trifluorophenyl)-1H-indole-3- sulfonamide 22.5 350  97I-76 15861- 36-6 57946- 56-2

N-(4-chloro-2-fluorophenyl)- 6-cyano-1H-indole-3- sulfonamide 33.3 348 90

D.2. Method C. Synthesis of5-chloro-N-(4-cyanophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide I-77

In a vial, a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine (24 mg, 0.15mmol) in acetonitrile (100 pL) was stirred and chlorosulfonic acid (115pl, 1.69 mmol) was added dropwise and the reaction mixture was heated to120° C. for 2h. After cooling to room temperature, pyridine (1 mL) wasadded. Then, a solution of 4-aminobenzonitrile (35 mg, 0.3 mmol) and4-dimethylaminopyridine (4 mg, 0.03 mmol) in acetonitrile (100 pL) wasadded. The reaction mixture was stirred at 80° C. for 3h, thenevaporated in a centrifugal evaporator. The residue was purified byreverse phase chromatography in basic mode with MS detection to afford 5mg of 5-chloro-N-(4-cyanophenyI)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide1-77.

Yield: 10%.

Basic LCMS Method 1 (ES-): 331 (M−H)-, 100% purity.

The following compounds in Table 5 were synthesized according to MethodC.

TABLE 5 Basic Basic LCMS LCMS Method Method 1 (ES−): Indoles AminesYield 1 (ES−): purity No XI X Structure Name (%) (M − H)− (%) I-78 143468-13-7 767-64-6

N-(2,1,3- benzothiadiazol-4- yl)-6-bromo-1H- pyrrolo[2,3- b]pyridine-3-sulfonamide  6.3 408  93 I-79  898746-50-4 873-74-5

N-(4- cyanophenyl)-5- iodo-1H- pyrrolo[2,3- b]pyridine-3- sulfonamide 5.7 423 100 I-80  143468-13-7 873-74-5

6-bromo-N-(4- cyanophenyl)-1H- pyrrolo[2,3- b]pyridine-3- sulfonamide 1.9 375  96 I-81  898746-50-4 367-30-6

N-(2,5- difluorophenyl)-5- iodo-1H- pyrrolo[2,3- b]pyridine-3-sulfonamide  6.9 434  88 I-82  898746-50-4 367-25-9

N-(2,4- difluorophenyl)-5- iodo-1H- pyrrolo[2,3- b]pyridine-3-sulfonamide 12   434 100 I-83  143468-13-7 21397-08-0

6-bromo-N-(2- chloro-3- fluorophenyl)-1H- pyrrolo[2,3- b]pyridine-3-sulfonamide 2  402 100 I-84  55052-27-2 14235-81-5

6-chloro-N-(4- ethynylphenyl)- 1H-pyrrolo[2,3- b]pyridine-3- sulfonamide 3.4 330  85 I-85  143468-13-7 14235-81-5

6-bromo-N-(4- ethynylphenyl)- 1H-pyrrolo[2,3- b]pyridine-3- sulfonamide 6.2 374  97 I-86  55052-27-2 367-25-9

6-chloro-N-(2,4- difluorophenyl)- 1H-pyrrolo[2,3- b]pyridine-3-sulfonamide  6.2 342  96 I-87  55052-27-2 21397-08-0

6-chloro-N-(2- chloro-3- fluorophenyl)-1H- pyrrolo[2,3- b]pyridine-3-sulfonamide  2.2 358 100 I-88  143468-13-7 367-30-6

6-bromo-N-(2,5- difluorophenyl)- 1H-pyrrolo[2,3- b]pyridine-3-sulfonamide  5.7 386  92 I-89  143468-13-7 372-39-4

6-bromo-N-(3,5- difluorophenyl)- 1H-pyrrolo[2,3- b]pyridine-3-sulfonamide  8.4 386 100 I-90  55052-27-2 367-30-6

6-chloro-N-(2,5- difluorophenyl)- 1H-pyrrolo[2,3- b]pyridine-3-sulfonamide  2.1 342 100 I-91  143468-13-7 367-25-9

6-bromo-N-(2,4- difluorophenyl)- 1H-pyrrolo[2,3- b]pyridine-3-sulfonamide  6.5 386 100 I-92  143468-13-7 57319-65-0

6-bromo-N-(3- oxo-1,3-dihydro- 2-benzofuran-5- yl)-1H- pyrrolo[2,3-b]pyridine-3- sulfonamide 3  406 100 I-93  55052-27-2 767-64-6

N-(2,1,3- benzothiadiazol-4- yl)-6-chloro-1H- pyrrolo[2,3- b]pyridine-3-sulfonamide 1  364 100 I-94  55052-27-2 29632-74-4

6-chloro-N-(2- fluoro-4- iodophenyl)-1H- pyrrolo[2,3- b]pyridine-3-sulfonamide  5.5 450 100 I-95  143468-13-7 367-34-0

6-bromo-N-(2,4,5- trifluorophenyl)- 1H-pyrrolo[2,3- b]pyridine-3-sulfonamide  2.1 404 100 I-96  55052-27-2 1668-84-4

N-(1,3- benzodioxol-4- yl)-6-chloro-1H- pyrrolo[2,3- b]pyridine-3-sulfonamide 20   350 100 I-97  143468-13-7 1668-84-4

N-(1,3- benzodioxol-4- yl)-6-bromo-1H- pyrrolo[2,3- b]pyridine-3-sulfonamide  2.2 394 100 I-98  898746-50-4 767-64-6

N-(2,1,3- benzothiadiazol-4- yl)-5-iodo-1H- pyrrolo[2,3- b]pyridine-3-sulfonamide  8.5 456 100 I-99  898746-50-4 106876-54-4

N-(2,2-difluoro- 1,3-benzodioxol- 4-yl)-5-iodo-1H- pyrrolo[2,3-b]pyridine-3- sulfonamide  3.6 478 100 I-100 55052-27-2 106876-54-4

6-chloro-N-(2,2- difluoro-1,3- benzodioxol-4- yl)-1H- pyrrolo[2,3-b]pyridine-3- sulfonamide  2.1 386  98 I-101 898746-50-4 29632-74-4

N-(2-fluoro-4- iodophenyl)-5- iodo-1H- pyrrolo[2,3- b]pyridine-3-sulfonamide  1.7 542 100 I-102 143468-13-7 106876-54-4

6-bromo-N-(2,2- difluoro-1,3- benzodioxol-4- yl)-1H- pyrrolo[2,3-b]pyridine-3- sulfonamide  0.6 430  95 I-103 898746-50-4 367-34-0

5-iodo-N-(2,4,5- trifluorophenylyl)- 1H-pyrrolo[2,3- b]pyridine-3-sulfonamide 21   452  94 I-104 143468-13-7 29632-74-4

6-bromo-N-(2- fluoro-4- iodophenyl)-1H- pyrrolo[2,3- b]pyridine-3-sulfonamide  4.7 494 100

D.3. Method D. Synthesis ofN-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide 1-105

A solution of indole (33.5 mg, 0.29 mmol), sulfur trioxide-pyridinecomplex (45.43 mg, 0.29 mmol) and pyridine (1 mL) were refluxed for 1 hat 120 ° C., then the mixture was cooled to room temperature, followedby evaporation of pyridine under vacuum. The resulting suspension wasdiluted with water (10 mL) and subsequently washed with diethyl ether(3×30 mL). The aqueous phase was then dried under high vacuum (or bylyophilization) to yield a solid residue. To the dry residue,triphenylphosphine (230 mg, 0.86 mmol), trichloroacetonitrile (123 mg,0.86 mmol), and dichloromethane (1 mL) were added and the resultingmixture was heated at 70 ° C. for 1 h, followed by the addition of the4-amino-3-fluorobenzonitrile (46.6 mg, 0.34 mmol) and 4-picoline (239mg, 2.57 mmol). The resulting mixture was stirred overnight at roomtemperature. Then the organic phase was diluted with DCM, washed withwater, dried over anhydrous magnesium sulfate and evaporated to dryness.The product was purified by column chromatography using petroleum ether(b.p. 60° C.): ethyl acetate, gradient from 4 : 1 to 3: 2 yielding acolorless oil, which on crystallization with acetone and petroleum ethergave 9 mg of N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide I-105,as a white powder.

Yield: 10%.

Neutral LCMS Method 3 (ES⁺): 316.05 (M-FH)+, 97% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.08 (s, 1H), 10.76 (s, 1H), 8.08 (d, J=3.1Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.70 (dd, J=10.7, 1.9 Hz, 1H),7.61-7.48 (m, 2H), 7.49-7.42 (m, 1H), 7.16-7.24 (m, 2H).

The following compounds were synthesized according to Method D:

N-(2,1,3-benzothiadiazol-4-yl)-1H-indole-3-sulfonamide I-106 from1H-indole CAS 120-72-9 and 2,1,3-benzothiadiazol-4-amine CAS 767-64-6

Yield: 15%.

Neutral LCMS Method 3 (ES⁺): 331.02 (M+H)⁺, 95% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 11.99 (d, J=3.3 Hz, 1H), 10.73 (s, 1H), 8.10(d, J=3.0 Hz, 1H), 7.87 (dd, J=8.1, 1.2 Hz, 1H), 7.65 (dd, J=8.8, 0.9Hz, 1H), 7.57 (dd, J=8.8, 7.4 Hz, 1H), 7.48 (dd, J=7.5, 0.9 Hz, 1H),7.39 -7.40 (m, 1H), 7.14-7.17 (m, 1H), 7.08-7.11 (m, 1H).

N-(2,1,3-benzothiadiazol-4-yl)-6-fluoro-1H-indole-3-sulfonamide I-107from 6-fluoro-1H-indole CAS 399-51-9 and 2,1,3-benzothiadiazol-4-amineCAS 767-64-6

Yield: 13%.

Neutral LCMS Method 3 (ES⁺): 349.02 (M+H)⁺, 95% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.02 (s, 1H), 10.80 (s, 1H), 8.09 (d, J=2.9Hz, 1H), 7.86 (dd, J=8.9, 5.3 Hz, 1 H), 7.71-7.62 (m, 1H), 7.58 (dd,J=8.8, 7.5 Hz, 1H), 7.47 (dd, J=7.4, 1.0 Hz, 1H), 7.19 (dd, J=9.7, 2.4Hz, 1H), 6.98-7.01 (m, 1H).

6-chloro-N-(4-cyano-2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamideI-108 from 6-chloro-1H-pyrrolo[2,3-b]pyridine CAS 55052-27-2 and4-amino-3-fluoro-benzonitrile CAS 63069-50-1

Yield: 5%.

Neutral LCMS Method 3 (ES⁺): 351 (M+H)⁺, 95.0% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.92 (d, J=3.4 Hz, 1H), 10.83 (s, 1H), 8.27(d, J=2.9 Hz, 1H), 8.22 (d, J=8.3 Hz, 1 H), 7.81-7.68 (m, 1H), 7.64-7.50(m, 2H), 7.37 (d, J=8.3 Hz, 1H).

N-(2,1,3-benzothiadiazol-4-yl)-6-chloro-1H-indole-3-sulfonamide I-109from 6-chloro-1H-indole CAS 17422-33-2 and 2,1,3-benzothiadiazol-4-amineCAS 767-64-6

Yield: 31%.

Neutral LCMS Method 3 (ES⁺): 364.99 (M+H)⁺, 99.0% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.08 (s, 1H), 10.80 (s, 1H), 8.12 (d, J=2.4Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.68 (dd, J=8.8, 0.9 Hz, 1H), 7.58 (dd,J=8.8, 7.4 Hz, 1H), 7.50-7.43 (m, 2H), 7.14 (dd, J=8.6, 1.9 Hz, 1H).

N-(2,1,3-benzothiadiazol-4-yl)-6-bromo-1H-indole-3-sulfonamide I-110from 6-bromo-1H-indole CAS 52415-29-9 and 2,1,3-benzothiadiazol-4-amineCAS 767-64-6

Yield: 27%.

Neutral LCMS Method 3 (ES⁺): 408.94 (M-FH)+, 94.0% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.07 (s, 1H), 10.80 (s, 1H), 8.10 (d, J=2.6Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.68 (dd, J=8.8, 0.9 Hz, 1H), 7.65-7.55(m, 2H), 7.46 (dd, J =7.5, 0.9 Hz, 1H), 7.26 (dd, J=8.6, 1.8 Hz, 1H).

N-(2,1,3-benzothiadiazol-4-yl)-7-bromo-1H-indole-3-sulfonamide I-111from 7-bromo-1H-indole CAS 51417-51-7 and 2,1,3-benzothiadiazol-4-amineCAS 767-64-6

Yield: 25%.

Neutral LCMS Method 3 (ES⁺): 408.94 (M-FH)+, 96.8% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.30 (d, J=3.5 Hz, 1H), 10.86 (s, 1H), 8.10(d, J=2.8 Hz, 1H), 7.88 (dd, J=8.0, 0.9 Hz, 1H), 7.68 (dd, J=8.8, 0.9Hz, 1H), 7.58 (dd, J=8.8, 7.4 Hz, 1H), 7.49 (dd, J=7.4, 0.9 Hz, 1H),7.41 (dd, J=7.7, 0.9 Hz, 1H), 7.06 (t, J=7.9 Hz, 1H).

N-(4-cyano-2-fluorophenyl)-6-methoxy-1 H-indole-3-sulfonamide I-112 from6-methoxy-1 H-indole CAS 3189-13-7 and 4-amino-3-fluoro-benzonitrile CAS63069-50-1

Yield: 18%.

Neutral LCMS Method 3 (ES⁺): 345.3 (M+H)⁺, 97.33% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 11.96-11.74 (m, 1H),10.69 (s, 1H), 7.93 (d,J=3.0 Hz, 1H), 7.76-7.63 (m, 2H), 7.60-7.46 (m, 2H), 6.93 (dd, J=2.3,0.6 Hz, 1 H), 6.82 (dd, J=8.8, 2.3 Hz, 1H), 3.76 (s, 3H).

N-(4-cyano-2-fluorophenyl)-6-fluoro-1H-indole-3-sulfonamide I-113 from6-fluoro-1 H-indole CAS 399-51-9 and 4-amino-3-fluoro-benzonitrile CAS63069-50-1

Yield: 21%.

Neutral LCMS Method 3 (ES⁺): 333.3 (M+H)⁺, 98.49% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 11.96-11.74 (m, 1H),10.69 (s, 1H), 7.93 (d,J=3.0 Hz, 1H), 7.76-7.63 (m, 2H), 7.60-7.46 (m, 2H), 6.93 (dd, J=2.3,0.6 Hz, 1 H), 6.82 (dd, J =8.8, 2.3 Hz, 1H), 3.76 (s, 3H).

6-bromo-N-(4-cyano-2-fluorophenyl)-1 H-indole-3-sulfonamide I-114 from6-bromo-1H-indole CAS 52415-29-9 and 4-amino-3-fluoro-benzonitrile CAS63069-50-1

Yield: 25%.

Neutral LCMS Method 3 (ES⁺): 394.2 (M+H)⁺, 99.34% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.23-12.10 (m, 1H), 10.77 (s, 1H), 8.09 (d,J=3.0 Hz, 1H), 7.79-7.70 (m, 2H), 7.66 (d, J=1.8 Hz, 1 H), 7.55 (dd,J=3.5, 1.6 Hz, 2H), 7.34 (dd, J=8.6, 1.8 Hz, 1H).

N-(4-cyano-2-fluorophenyl)-7-methoxy-1 H-indole-3-sulfonamide I-115 from7-methoxy-1 H-indole CAS 3189-22-8 and 4-amino-3-fluoro-benzonitrile CAS63069-50-1

Yield: 17%.

Neutral LCMS Method 3 (ES⁺): 345.3 (M+H)⁺, 100% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.46-12.02 (m, 1H), 10.72 (s, 1H), 7.91 (d,J=3.1 Hz, 1H), 7.70 (dd, J=10.8, 1.8 Hz, 1H), 7.61-7.52 (m, 2H), 7.40(d, J=8.1 Hz, 1H), 7.10 (t, J=7.9 Hz, 1 H), 6.79 (d, J=7.8 Hz, 1H), 3.90(s, 3H).

6-chloro-N-(4-cyano-2-fluorophenyl)-1 H-indole-3-sulfonamide I-116 from6-chloro-1H-indole CAS 17422-33-2 and 4-amino-3-fluoro-benzonitrile CAS63069-50-1

Yield: 28′)/0.

Neutral LCMS Method 3 (ES⁺): 349.7 (M+H)⁺, 100% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.17 (d, J=3.3 Hz, 1H), 10.77 (s, 1H), 8.10(d, J=2.9 Hz, 1H), 7.82 (d, J=8.6 Hz, 1 H), 7.75-7.71 (m, 1H), 7.57-7.53(m, 2H), 7.52 (s, 1 H), 7.23 (dd, J=8.6, 1.9 Hz, 1 H).

7-chloro-N-(4-cyano-2,5-difluorophenyI)-1H-indole-3-sulfonamide I-117from 7-chloro-1 H-indole CAS 53924-05-3 and4-amino-2,5-difluoro-benzonitrile CAS 112279-61-5

Yield: 42%.

Neutral LCMS Method 3 (ES⁺): 337.99 (M+H)⁺, 98% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.65 (s, 1H), 11.25 (s, 1 H), 8.35 (d,J=3.1 Hz, 1H), 7.89-7.80 (m, 2H), 7.49 (dd, J=10.9, 6.3 Hz, 1H), 7.36(dd, J=7.7, 0.9 Hz, 1H), 7.23 (t,

J=7.9 Hz, 1H).

D.4. Method E. Synthesis ofN-(4-chloro-2,5-difluorophenyl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamideI-118

To a solution of 1H-pyrrolo[3,2-H]guinoline-3-sulfonyl chloride (140 mg,0.52 mmol) in pyridine (1.5 mL) was added 4-chloro-2,5-difluoroaniline(90 mg, 0.55 mmol). The reaction mixture was stirred at room temperaturefor 4h and then evaporated to dryness. The residue was triturated in amixture of water/acetonitrile (8/2) and sonicated. The solid suspensionwas filtered, rinsed with water, dried under vacuum at 35° C., to afford105 mg ofN-(4-chloro-2,5-difluorophenyI)-1H-pyrrolo[3,2-h]guinoline-3-sulfonamideI-118, as a beige solid.

Yield: 50%.

Basic LCMS Method 1 (ES⁺): 394 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (s, 1H), 10.51 (s, 1H), 8.93 (dd,J=4.4, 1.6 Hz, 1H), 8.46 (dd, J=8.3, 1.6 Hz, 1H), 8.04-7.65 (m, 3H),7.59 (m, 1 H), 7.51 (dd, J=9.8, 6.8 Hz, 1H), 7.40 (dd, J=10.4, 7.0 Hz,1H).

The following compounds in Table 6 may be synthesized according to amethod analogous to Method E.

TABLE 6 Sulfonyl chlorides Conditions, N° XII Amines X Time Purificationconditions Yield (%) I-119 XII-1 767-63-5 rt, 4 h — 41 I-120 XII-2873-74-5 70° C., 8 h 10-35% EtOAc/Hexane 8 I-121 XII-3 452-80-2 80° C.,4 h Basic prep LCMS Method 37 1 I-122 XII-4 80936-82-9 80° C., 16 h 2%MeOH in DCM 57 I-123 XII-4 106876-54-4 80° C., 5 h 40% EtOAc/Hexane 49I-124 XII-4 7251-09-4 80° C., 4 h 0-30% EtOAc/Hexane 19 I-125 XII-4120934-03-4 80° C., 4 h 20-24% EtOAc/Hexane 37 I-126 XII-4 177476-76-580° C., 3 h 15-20% EtOAc/Hexane 37 I-127 XII-4 X-1 80° C., 16 h 1% MeOHin DCM 18 I-128 XII-4 21717-95-3 80° C., 16 h 30% EtOAc/Hexane 58 I-129XII-4 42409-58-5 70° C., 16 h 10% MeOH in DCM 22 I-130 XII-4 X-2 60° C.,1 h 10-30% EtOAc/Hexane 59 I-131 XII-4 X-3 85° C., 16 h 0-10%EtOAc/Hexane 12 I-132 XII-4 X-4 80° C., 16 h 20-30% EtOAc/Hexane 16I-133 XII-5 873-74-5 80° C., 16 h 0.4% MeOH in DCM 22 I-134 XII-6873-74-5 80° C., 16 h 50% EtOAc/Hexane 45 I-135 XII-6 120934-03-4 80°C., 16 h 60% EtOAc/Hexane 34 I-136 XII-6 367-34-0 80° C., 16 h 20%EtOAc/Hexane 82 I-137 XII-6 106876-54-4 80° C., 16 h 15-25% EtOAc/Hexane21 I-138 XII-4 369-35-7 85° C., 4 h 50% EtOAc/Hexane 38 (crude) I-139XII-24 873-74-5 85° C., 16 h 20% EtOAc/Hexane 5 I-140 XII-4 29632-74-470° C., 2 h Basic prep LCMS Method 23 1 I-141 XII-4 57946-56-2 80° C., 2h Basic prep LCMS Method 29 1 I-142 XII-4 X-6 80° C., 5 h 20-40%EtOAc/Petroleum ether then Neutral RP-HPLC 7 Method 2 I-143 XII-4247071-37-0 80° C., 5 h 20-40% EtOAc/Petroleum ether then NeutralRP-HPLC 11 Method 2 I-144 XII-7 X-5 80° C., 3 h 20-40% EtOAc/Petroleum14 ether I-145 XII-8 112279-61-5 80° C., 18 h 5-25% 26 EtOAc/CyclohexaneI-146 XII-9 112279-61-5 80° C., 18 h 5-25% 11 EtOAc/Cyclohexane I-147XII-4 874-37-3 rt, 8 h 5-25% 10 EtOAc/Cyclohexane I-148 XII-10112279-61-5 80° C., 2 h 5-25% 32 EtOAc/Cyclohexane I-149 XII-1053312-80-4 80° C., 2 h 5-25% 46 EtOAc/Cyclohexane I-150 XII-1063069-50-1 80° C., 2 h 5-25% 16 EtOAc/Cyclohexane I-151 XII-3112279-61-5 80° C., 2 h 5-25% 28 EtOAc/Cyclohexane I-152 XII-363069-50-1 80° C., 2 h 5-25% 58 EtOAc/Cyclohexane I-153 XII-11112279-61-5 80° C., 2 h 5-25% 68 EtOAc/Cyclohexane 5-25% I-154 XII-1163069-50-1 80° C., 2 h EtOAc/Cyclohexane 73 5-25% I-155 XII-3 767-64-680° C., 2 h EtOAc/Cyclohexane 42 5-25% I-156 XII-11 767-64-6 80° C., 2 hEtOAc/Cyclohexane 75 I-157 XII-3 874-37-3 80° C., 2 h 5-25% 65EtOAc/Cyclohexane I-158 XII-10 874-37-3 80° C., 2 h 5-25% 44EtOAc/Cyclohexane I-159 XII-3 873-74-5 80° C., 2 h 5-25% 22EtOAc/Cyclohexane I-160 XII-3 X-5 80° C., 2 h 5-25% 33 EtOAc/CyclohexaneI-161 XII-4 X-10 80° C., 2 h 5-25% 28 EtOAc/Cyclohexane I-162 XII-4 X-570° C., 16 h 20% EtOAc/Petroleum 23 ether I-163 XII-4 X-9 70° C., 16 h33% EtOAc/Petroleum 18 ether I-164 XII-12 112279-61-5 70° C., 16 h 40%EtOAc/Petroleum 52 ether I-165 XII-13 112279-61-5 70° C., 16 h 40%EtOAc/Petroleum 55 ether I-166 XII-12 767-64-6 70° C., 16 h 40%EtOAc/Petroleum 65 ether I-167 XII-14 112279-61-5 70° C., 16 h 40%EtOAc/Petroleum 44 ether I-168 XII-12 63069-50-1 70° C., 16 h 40%EtOAc/Petroleum 63 ether I-169 XII-13 874-37-3 80° C., 3 h 40%EtOAc/Petroleum 62 ether I-170 XII-15 63069-50-1 70° C., 16 h 40%EtOAc/Petroleum 43 ether then Neutral RP- HPLC Method 2 I-171 XII-13873-74-5 70° C., 16 h 40% EtOAc/Petroleum 35 ether then Neutral RP- HPLCMethod 2 I-172 XII-13 X-5 80° C., 3 h 40% EtOAc/Petroleum 65 ether I-173XII-16 367-24-8 70° C., 16 h 40% EtOAc/Petroleum 61 ether I-174 XII-1657946-56-2 70° C., 16 h 40% EtOAc/Petroleum 64 ether I-175 XII-31268392-91-1 70° C., 16 h 40% EtOAc/Petroleum 35 ether I-176 XII-7112279-61-5 80° C., 5 h 50% EtOAc/Petroleum 29 ether I-177 XII-1763069-50-1 rt, 5 h Neutral RP-HPLC Method 4 2 I-178 XII-7 873-74-5 rt,16 h Neutral RP-HPLC Method 48 2 I-179 XII-7 874-37-3 rt, 16 h NeutralRP-HPLC Method 40 2 I-180 XII-4 3544-25-0 80° C., 16 h 33% EtOAc/Petroleum 8 ether I-181 XII-4 20925-27-3 80° C., 16 h 33% EtOAc/Petroleum 5 ether I-182 XII-4 110301-23-0 80° C., 16 h 33% EtOAc/Petroleum 7 ether 25-100% I-183 XII-6 874-37-3 80° C., 2 hEtOAc/Cyclohexane 19 I-184 XII-18 112279-61-5 80° C., 2 h 25-100% 6EtOAc/Cyclohexane I-185 XII-4 112279-61-5 80° C., 2 h 25-100% 60EtOAc/Cyclohexane I-186 XII-18 767-64-6 80° C., 2 h 25-100% 30EtOAc/Cyclohexane I-187 XII-16 112279-61-5 80° C., 2 h 25-100% 7EtOAc/Cyclohexane I-188 XII-6 112279-61-5 80° C., 2 h 25-100% 6EtOAc/Cyclohexane I-189 XII-18 63069-50-1 80° C., 2 h 25-100% 3EtOAc/Cyclohexane I-190 XII-18 873-74-5 80° C., 2 h 25-100% 8EtOAc/Cyclohexane I-191 XII-3 246847-98-3 70° C., 16 h 33% EtOAc/Petroleum 21 ether I-192 XII-18 874-37-3 80° C., 2 h 25-100% 16EtOAc/Cyclohexane I-193 XII-6 X-5 80° C., 2 h 25-100% 16EtOAc/Cyclohexane I-194 XII-4 X-11 rt, 4 h 30-70% EtOAc/Hexane 10 I-195XII-4 X-12 80° C., 16 h 40% EtOAc/Hexane 11 I-196 XII-25 367-34-0 80°C., 3 h 10-30% EtOAc/Hexane 17 I-197 XII-4 X-13 65° C., 3 h 25-30%EtOAc/Hexane 12 I-198 XII-24 2613-30-1 70° C., 16 h 10-20% EtOAc/Hexane1 I-199 XII-4 X-14 80° C., 4 h 30% EtOAc/Hexane 6 I-200 XII-4 X-15 80°C., 3 h 50% EtOAc/Hexane 6 I-242 XII-26 2613-30-1 80° C., 16 h 40%EtOAc/Hexane 11 I-243 XII-4 X-17 70° C., 4 h 20-40% EtOAc/Hexane 33I-244 XII-25 2613-30-1 80° C., 16 h 30% EtOAc/Hexane 20 I-245 XII-4 X-16DMAP cat., 40% EtOAc/Hexane 2 80° C., 16 h I-246 XII-4 X-18 70° C., 5 h10-20% EtOAc/Hexane 32 I-247 XII-27 2613-30-1 80° C., 8 h 20%EtOAc/Hexane 8 I-248 XII-28 2613-30-1 80° C., 16 h 10-40% EtOAc/Hexane 8I-249 XII-29 2613-30-1 DMAP cat., 40% EtOAc/Hexane 51 80° C., 5 h I-251XII-30 2613-30-1 DMAP cat., 40% EtOAc/Hexane 10 80° C., 12 h I-252 XII-4X-19 DMAP cat., 40% EtOAc/Hexane 6 90° C., 16 h I-253 XII-4 X-20 DMAPcat., 40% EtOAc/Hexane 10 90° C., 14 h I-254 XII-4 X-21 DMAP cat., 40%EtOAc/Hexane 4 80° C., 18 h I-255 XII-4 X-22 DMAP cat., 40% EtOAc/Hexane14 80° C., 14 h I-257 XII-4 X-23 80° C., 16 h 40% EtOAc/Hexane 25 I-258XII-31 63069-50-1 80° C., 16 h 30-70% EtOAc/Hexane 9 I-259 XII-24112279-60-4 70° C., 16 h 0-5% EtOAc/Hexane 12 I-260 XII-4 X-24 70° C., 6h 30-35% EtOAc/Hexane 47 I-262 XII-32 2613-30-1 80° C., 16 h 30%EtOAc/Hexane 46 I-263 XII-31 2613-30-1 80° C., 16 h 10-30% EtOAc/Hexane27 I-264 XII-4 X-25 80° C., 16 h 30-90% EtOAc/Hexane 13 I-265 XII-4 X-26DMAP cat., 10% MeOH in DCM 27 80° C., 16 h I-289 XII-3 1441723-24-5 rt,4 h 20% EtOAc/petroleum 46 ether I-304 XII-3 X-14 120° C., 5 h 30-50%EtOAc/heptane 7 then Basic prep LCMS Method 1 I-305 XII-1 112279-60-4rt, 48 h — 5 I-306 XII-1 1008112-39-7 rt, 48 h Basic prep LCMS Method 21 I-309 XII-25 X-21 80° C., 12 h Basic prep LCMS Method 19 1 I-311XII-38 873-74-5 70° C., 1 h 10-20% EtOAc/Hexane 12 I-312 XII-382613-30-1 70° C., 16 h 10-20% EtOAc/Hexane 44 I-313 XII-38 X-23 70° C.,16 h 15-20% EtOAc/Hexane 12 I-314 XII-38 X-21 80° C., 16 h 8-12%EtOAc/Hexane 5 I-315 XII-38 X-22 80° C., 16 h 10-15% EtOAc/Hexane 21I-319 XII-26 X-21 Cat. DMAP, Basic prep LC 3 80° C., 16 h I-320 XII-6X-22 Cat. DMAP, 50% EtOAc/Hexane 14 80° C., 24 h I-321 XII-29 X-21 Cat.DMAP, 40% EtOAc/Hexane 34 80° C., 16 h I-322 XII-29 X-22 Cat. DMAP,Basic prep LC 12 100° C., 24 h I-323 XII-6 X-20 Cat. DMAP, 40%EtOAc/Hexane 9 80° C., 16 h I-324 XII-28 X-22 Cat. DMAP, 65%EtOAc/Hexane 25 90° C., 32 h I-325 XII-6 X-19 Cat. DMAP, Basic prep LC 3100° C., 24 h I-326 XII-39 246847-98-3 80° C., 2 h 50% EtOAc/heptane 9I-327 XII-4 X-27 80° C., 4 h 40-45% EtOAc/Hexane 56 I-328 XII-1 X-21120° C., 2 h 40-80% EtOAc/heptane 10 I-329 XII-3 X-21 120° C., 4 h — 73I-334 XII-40 63069-50-1 Cat. DMAP, 25% EtOAc/Hexane 22 85° C., 16 hI-339 XII-31 X-21 Cat. DMAP, Basic prep LC 12 100° C., 24 h I-340 XII-41X-21 Cat. DMAP, 40% EtOAc/Hexane 31 80° C., 16 h I-341 XII-29 63069-50-1100° C., 24 h 40-80% EtOAc/Hexane 72 I-342 XII-24 X-23 70° C., 16 hBasic prep LC 18 I-343 XII-28 63069-50-1 Cat. DMAP, 65% EtOAc/Hexane 1280° C., 16 h I-344 XII-4 X-28 Cat. DMAP, 40% EtOAc/Hexane 25 90° C., 12h I-345 XII-4 X-29 80° C., 16 h 40-60% EtOAc/Hexane 17 I-346 XII-24 X-2170° C., 16 h 15-20% EtOAc/Hexane 4 then Basic prep LC I-347 XII-422613-30-1 80° C., 16 h 25-40% EtOAc/Hexane 15 I-348 XII-4 X-30 Cat.DMAP, Basic prep LC 22 100° C., 24 h I-349 XII-4 X-31 Cat. DMAP, 35-48%EtOAc/Hexane 6 100° C., 12 h I-350 XII-4 X-32 Cat. DMAP, 50-60%EtOAc/Hexane 5 100° C., 16 h I-351 XII-40 X-22 70° C., 16 h 40-50%EtOAc/Hexane 47 I-354 XII-26 X-22 Cat. DMAP, 40% EtOAc/Hexane 46 80° C.,16 h I-355 XII-26 X-30 Cat. DMAP, Basic prep LC 8 80° C., 18 h I-356XII-43 X-21 Cat. DMAP, 30% EtOAc/Hexane 10 80° C., 16 h I-357 XII-44X-21 Cat. DMAP, 30% EtOAc/Hexane 11 90° C., 16 h I-358 XII-26 X-29 Cat.DMAP, 40% EtOAc/Hexane 32 80° C., 16 h I-360 XII-1 X-23 rt, 6 h — 72I-361 XII-1 X-33 rt, 20 h — 63 I-362 XII-1 X-34 rt, 6 h — 61 I-364 XII-4X-35 Cat. DMAP, 35% EtOAc/Hexane 16 100° C., 16 h I-365 XII-4 X-36 Cat.DMAP, 35% EtOAc/Hexane 10 80° C., 18 h I-366 XII-46 X-29 Cat. DMAP,45-55% EtOAc/Hexane 15 80° C., 12 h I-367 XII-47 X-30 90° C., 16 h50-60% EtOAc/Hexane 7

N-(2,1,3-benzoxadiazol-4-yl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamideI-119

Basic LCMS Method 1 (ES⁺): 366 (M+H)⁺, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 13.29 (s, 1H), 11.35 (s, 1H), 8.90 (dd,J=4.4, 1.6 Hz, 1H), 8.42 (dd, J=8.3, 1.6 Hz, 1H), 8.14 (s, 1H), 8.08 (d,J=8.7 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.63-7.42 (m, 3H), 7.32 (d, J=7.2Hz, 1 H).

N-(4-cyanophenyl)-5,6-difluoro-1 H-indole-3-sulfonamide I-120

Basic LCMS Method 2 (ES⁺): 334 (M+H)⁺, 99% purity. ¹H NMR (400 MHz,DMSO-d₆) δ 7.24 (d, J=8.7 Hz, 2H) 7.52 (dd, J=10.7, 7.0 Hz, 1H) 7.65 (d,J=8.7 Hz, 2H) 7.74 (dd, J=10.9, 7.9 Hz, 1H) 8.21 (d, J=2.8 Hz, 1H) 10.95(s, 1H) 12.26 (s, 1H).

N-(2-fluoro-4-methylphenyl)-1 H-benzo[g]indole-3-sulfonamide I-121

Basic LCMS Method 1 (ES⁻F): 355 (M+H)⁺, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.83 (s, 1H), 9.78 (s, 1H), 8.40 (dd,J=8.2, 1.0 Hz, 1H), 7.98 (dd, J=8.2, 1.2 Hz, 1H), 7.83 -7.90 (m, 2H),7.68-7.56 (m, 2H), 7.51 (ddd, J=8.1, 6.9, 1.2 Hz, 1H), 7.15 (t, J=8.2Hz, 1H), 6.94-6.79 (m, 2H), 2.18 (s, 3H)6-chloro-N-(4-(methoxymethyl)phenyl)-1H-indole-3-sulfonamide I-122

Basic LCMS Method 2 (ES⁻): 349 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.19 (s, 3H) 4.22 (s, 2H) 7.01-7.06 (m, 2H)7.08-7.13 (m, 2H) 7.20 (dd, J=8.56, 1.71 Hz, 1 H) 7.48 (d, J=1.47 Hz,1H) 7.80 (d, J=8.56 Hz, 1H) 7.98 (s, 1H) 10.19 (brs, 1H) 12.02 (brs,1H).

6-chloro-N-(2,2-difluoro-1,3-benzodioxo1-4-yl)-1H-indole-3-sulfonamideI-123

Basic LCMS Method 2 (ES⁻): 385 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.95 (d, J=7.82 Hz, 1H) 7.06 (t, J=8.31 Hz,1H) 7.11 -7.15 (m, 1H) 7.18 (dd, J=8.56, 1.71 Hz, 1H) 7.52 (d, J=1.47Hz, 1H) 7.64 (d, J=8.80 Hz, 1H) 7.94 (d, J=2.93 Hz, 1H) 10.34 (s, 1H)12.11 (brs, 1H).

6-chloro-N-(4-cyano-3-methoxyphenyl)-1H-indole-3-sulfonamide I-124

Basic LCMS Method 2 (ES⁻): 360 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.79 (s, 3H) 6.76 (d, J=8.31 Hz, 1 H) 6.87(s, 1 H) 7.26 (d, J=8.56 Hz, 1H) 7.44-7.56 (m, 2H) 7.83 (d, J=8.80 Hz,1H) 8.24 (s, 1H) 10.96 (s, 1H) 12.20 (brs, 1H).

6-chloro-N-(2,2,6-trifluoro-1,3-benzodioxo1-5-yl)-1H-indole-3-sulfonamideI-125

Basic LCMS Method 2 (ES⁻): 403 (M−H)⁻, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.18 (dd, J=8.56, 1.71 Hz, 1H) 7.29 (d,J=6.36 Hz, 1H) 7.41 (d, J=8.80 Hz, 1H) 7.50 (s, 1H) 7.68 (d, J=8.80 Hz,1H) 7.89 (d, J=2.93 Hz, 1H) 10.06 (s, 1H) 12.06 (brs, 1H).

6-chloro-N-(4-cyano-2-methoxyphenyl)-1H-indole-3-sulfonamide I-126

Basic LCMS Method 2 (ES⁻): 360 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.62 (s, 3H) 7.22 (dd, J=8.80, 1.47 Hz, 1H)7.28-7.33 (m, 2H) 7.46 (d, J=8.31 Hz, 1 H) 7.51 (s, 1 H) 7.86 (d, J=8.31Hz, 1 H) 8.05 (d, J=2.45 Hz, 1H) 9.85 (s, 1H) 12.10 (brs, 1H).

6-chloro-N-(7-fluoro-2,1,3-benzothiadiazol-4-yl)-1H-indole-3-sulfonamideI-127

Basic LCMS Method 2 (ES⁻): 381 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.13 (d, J=8.80 Hz, 1H) 7.38-7.42 (m, 2H)7.44 (s, 1H) 7.76 (d, J=8.31 Hz, 1H) 8.02 (brs, 1H) 10.72 (s, 1H) 12.05(brs, 1H).

6-chloro-N-(3-fluoropyridin-2-yI)-1H-indole-3-sulfonamide I-128

Basic LCMS Method 2 (ES⁻F): 326 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.02-7.08 (m, 1H) 7.22 (d, J=8.31 Hz, 1H)7.52 (s, 1H) 7.61 (t, J=9.29 Hz, 1H) 7.87 (d, J=7.83 Hz, 1H) 7.96-8.02(m, 1H) 8.10 (s, 1H) 10.86 (s, 1H) 12.09 (s, 1H).

N-(5-bromo-3-methoxypyridin-2-yI)-6-chloro-1H-indole-3-sulfonamide I-129

Basic LCMS Method 2 (ES⁺): 416 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.78 (s, 3H) 7.21 (dd, J=8.56, 1.71 Hz, 1H)7.50 (s, 2H) 7.79 (d, J=1.96 Hz, 1H) 7.94 (d, J=8.31 Hz, 1H) 8.09 (d,J=2.45 Hz, 1H) 10.25 (s, 1H) 12.06 (brs, 1H).

N-(7-bromo-2,2-difluoro-1,3-benzodioxo1-4-yl)-6-chloro-1H-indole-3-sulfonamideI-130

Basic LCMS Method 2 (ES⁻): 463 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.91 (d, J=8.80 Hz, 1H) 7.19 (d, J=8.31 Hz,1H) 7.30 (d, J=9.29 Hz, 1H) 7.48-7.57 (m, 1H) 7.64-7.72 (m, 1H) 7.94 (d,J=2.45 Hz, 1H) 10.44 (brs, 1H) 12.13 (brs, 1H).

6-chloro-N-(5-fluoro-2,1,3-benzothiadiazol-4-yl)-1H-indole-3-sulfonamideI-131

Basic LCMS Method 2 (ES⁻F): 383 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.04 (dd, J=8.80, 1.96 Hz, 1H) 7.40 (d,J=8.80 Hz, 1H) 7.48 (d, J=1.47 Hz, 1H) 7.72 (t, J=9.78 Hz, 1H) 7.83 (d,J=1.96 Hz, 1H) 8.05 (dd, J=9.29, 4.40 Hz, 1H) 10.13 (s, 1H) 11.98 (brs,1H).

6-chloro-N-(6-cyano-2,2-difluoro-1,3-benzodioxo1-4-yl)-1H-indole-3-sulfonamideI-132

Basic LCMS Method 2 (ES⁻): 410.00 (M−H)⁻, 92% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.21 (dd, J=8.56, 1.71 Hz, 1H) 7.45 (s, 1H)7.52 (d, J=1.47 Hz, 1H) 7.65 (d, J=8.80 Hz, 1H) 7.78 (s, 1H) 8.10 (d,J=2.93 Hz, 1H) 10.82 (brs, 1H) 12.20 (brs, 1H).

N-(4-cyanophenyl)-6-cyclopropyl-1 H-indole-3-sulfonamide I-133

Basic LCMS Method 2 (ES⁻): 336.00 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 0.58-0.69 (m, 2H) 0.86-0.98 (m, 2H)1.91-2.02 (m, 1H) 6.90 (d, J=8.31 Hz, 1H) 7.12 (s, 1H) 7.19 (d, J=8.31Hz, 2H) 7.59 (d, J=8.80 Hz, 2H) 7.67 (d, J=8.31 Hz, 1H) 8.03 (brs, 1H)10.92 (brs, 1H) 11.87 (brs, 1H).

6-bromo-N-(4-cyanophenyl)-1H-indole-3-sulfonamide I-134

¹H NMR (400 MHz, DMSO-d₆) δ 7.23 (d, J=8.31 Hz, 2H) 7.36 (d, J=8.80 Hz,1 H) 7.59 -7.67 (m, 3H) 7.74-7.79 (m, 1H) 8.17 (s, 1H) 10.98 (brs, 1H)12.19 (brs, 1H).

6-bromo-N-(2.2.6-trifluoro-1,3-benzodioxo1-5-yl)-1H-indole-3-sulfonamideI-135

Basic LCMS Method 2 (ES⁺): 448.80 (M+H)⁺, 86% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.34 (d, J=6.40 Hz, 1H) 7.43 (d, J=8.80 Hz,1H) 7.71 (d, J=8.80 Hz, 1H) 7.95 (d, J=8.80 Hz, 1H) 8.03 (s, 1H) 8.17(brs, 1H) 10.20 (brs, 1H) 12.51 (brs, 1H).

6-bromo-N-(2,4,5-trifluorophenyl)-1 H-indole-3-sulfonamide I-136

Basic LCMS Method 2 (ES⁺): 405.00 (M+H)⁺, 94% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.31-7.36 (m, 2H) 7.44-7.51 (m, 1H)7.63-7.68 (m, 2H) 7.94 (d, J=2.93 Hz, 1H) 10.21 (s, 1H) 12.11 (brs, 1H).

6-bromo-N-(2,2-difluoro-1,3-benzodioxo1-4-yl)-1H-indole-3-sulfonamideI-137

Basic LCMS Method 2 (ES⁺): 431.00 (M+H)⁺, 93% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.94 (dd, J=8.31, 0.98 Hz, 1H) 7.06 (t,J=8.31 Hz, 1H) 7.11-7.15 (m, 1H) 7.28-7.32 (m, 1H) 7.60 (d, J=8.80 Hz,1H) 7.66 (d, J=1.47 Hz, 1H) 7.93 (d, J=2.93 Hz, 1H) 10.34 (s, 1H) 12.11(brs, 1H).

6-chloro-N-(2-fluoro-4-nitro-phenyl)-1 H-indole-3-sulfonamide I-138

Basic LCMS Method 2 (ES⁻): 368.00 (M−H)⁻, 39% purity.

6-chloro-N-(4-cyanophenyl)-1-benzofuran-3-sulfonamide I-139

Basic LCMS Method 2 (ES⁻): 331.00 (M−H)⁻, 99% purity. ¹H NMR (400 MHz,DMSO-d₆) δ 7.27 (d, J=8.31 Hz, 2H) 7.48-7.57 (m, 1 H) 7.70 (d, J=8.31Hz, 2H) 7.84 (s, 1H) 7.96 (s, 1H) 8.93 (s, 1H) 11.44 (brs, 1H).

6-chloro-N-(2-fluoro-4-iodophenyl)-1 H-indole-3-sulfonamide I-140

Basic LCMS Method 1 (ES⁺): 451 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 1H), 10.11 (s, 1H), 7.91 (d, J=2.4Hz, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.54-7.47 (s, dd , 2H), 7.44 (dd,J=8.4, 1.8 Hz, 1 H), 7.21 (dd, J =8.6, 1.9 Hz, 1 H), 7.08 (t, J=8.4 Hz,1 H).

6-chloro-N-(4-chloro-2-fluorophenyl)-1H-indole-3-sulfonamide I-141

Basic LCMS Method 1 (ES⁻): 357 (M−H)⁻, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 1H), 10.10 (s, 1H), 7.89 (d, J=2.1Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 7.36-7.25 (m,2H), 7.24-7.12 (m, 2H).

N-(2,1,3-benzoselenadiazol-4-yl)-6-chloro-1H-indole-3-sulfonamide I-142

Neutral LCMS Method 3 (ES⁺): 412.93 (M+H)⁺, 98% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.07 (s, 1H), 10.29 (s, 1H), 8.12 (s, 1H),7.85 (d, J=8.6 Hz, 1H), 7.46-7.44 (m, 1 H), 7.44-7.42 (m, 1H), 7.41 (d,J=9.0 Hz, 1 H), 7.27 (dd, J =6.5, 1.7 Hz, 1H), 7.13 (dd, J=8.6, 1.9 Hz,1H).

6-chloro-N-(4-cyano-2-fluoro-5-methoxyphenyI)-1H-indole-3-sulfonamideI-143

Neutral LCMS Method 3 (ES⁺): 379.02 (M+H)⁺, 96% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.13 (s, 1H), 10.83 (s, 1H), 8.15 (d, J=2.3Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.60-7.46 (m, 2H), 7.23 (dd, J=8.6, 1.9Hz, 1H), 7.12 (d, J =6.5 Hz, 1H), 3.78 (s, 3H).

6-chloro-N-(6-fluoro-2,1,3-benzothiadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamideI-144

Neutral LCMS Method 3 (ES⁺): 383.97 (M+H)⁺, 99% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.89 (s, 1H), 10.79 (s, 1H), 8.36 (d, J=2.8Hz, 1H), 8.29 (d, J=8.3 Hz, 1H), 7.94-7.79 (m, 2H), 7.36 (d, J=8.3 Hz,1H).

N-(4-cyano-2,5-difluorophenyI)-1H-indole-3-sulfonamide I-145

Neutral LCMS Method 3 (ES⁺): 334.03 (M+H)⁺, 99% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.17 (s, 1H), 11.16 (s, 1H), 8.27 (d, J=3.1Hz, 1H), 7.90-7.86 (m, 1H), 7.83 (dd, J=10.3, 6.0 Hz, 1H), 7.51-7.42 (m,2H), 7.23-7.24(m, 2H).

N-(4-cyano-2,5-difluorophenyI)-6-(2-methoxyethoxy)-1H-indole-3-sulfonamideI-146

Neutral LCMS Method 3 (ES⁺): 408.07 (M+H)⁺, 99% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 11.95 (s, 1H), 11.13 (s, 1H), 8.12 (d, J=3.0Hz, 1H), 7.84 (dd, J=10.2, 5.9 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.43(dd, J=11.0, 6.3 Hz, 1H), 6.96 (d, J=2.2 Hz, 1H), 6.87 (dd, J=8.8, 2.3Hz, 1H), 4.19-3.99 (m, 2H, CH2), 3.66 (dd, J =5.6, 3.6 Hz, CH2), 3.30(s, 3H, CH₃).

N-(2,1,3-benzothiadiazol-5-yl)-6-chloro-1H-indole-3-sulfonamide I-147

Neutral LCMS Method 3 (ES⁺): 364.98 (M+H)⁺, 99% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.14 (s, 1H), 10.95-10.90 (m, 1H), 8.25 (s,1H), 7.92 (dd, J=9.5, 0.7 Hz, 1H), 7.87 (d, J=8.6 Hz, 1H), 7.60 (dd,J=2.1, 0.7 Hz, 1H), 7.52-7.46 (m, 2H), 7.24 (dd, J=8.6, 1.9 Hz, 1H).

N-(4-cyano-2,5-difluorophenyI)-1,6,7,8-tetrahydrocyclopenta[g]indole-3-sulfonamideI-148

Neutral LCMS Method 3 (ES⁺): 374.06 (M+H)⁺, 98% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.02 (s, 1H), 11.14 (s, 1H), 8.21 (d, J=3.0Hz, 1H), 7.82 (dd, J=10.3, 5.9 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.44(dd, J=11.1, 6.3 Hz, 1H), 7.11 (d, J=8.1 Hz, 1H), 3.01 (t, J=7.4 Hz,2H), 2.94 (t, J=7.4 Hz, 2H), 2.10 (p, J=7.4 Hz, 2H).

N-(4-cyano-3-fluorophenyl)-1,6,7,8-tetrahydrocyclopenta[g]indole-3-sulfonamideI-149

Neutral LCMS Method 3 (ES⁺): 356.07 (M+H)⁺, 95% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.12 (s, 1H), 11.19 (s, 1H), 8.18 (d, J=3.1Hz, 1H), 7.68 (dd, J=8.6, 7.6 Hz, 1H), 7.61 (dd, J=8.1, 0.9 Hz, 1H),7.13-7.07 (m, 2H), 7.04 (dd,

J=8.6, 2.1 Hz, 1H), 3.01 (t, J=7.4 Hz, 2H), 2.93 (t, J=7.4 Hz, 2H), 2.09(p, J=7.4 Hz, 2H).

N-(4-cyano-2-fluorophenyl)-1,6,7,8-tetrahydrocyclopenta[g]indole-3-sulfonamideI-150

Neutral LCMS Method 3 (ES⁺): 356.07 (M+H)⁺, 98% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.05 (s, 1H), 10.72 (s, 1H), 8.01 (d, J=3.1Hz, 1H), 7.71 (dd, J=10.7, 1.8 Hz, 1H), 7.62 (dd, J=8.1, 0.8 Hz, 1H),7.58 (dd, J=8.6, 7.8 Hz, 1H), 7.55-7.52 (m, 1H), 7.08 (d, J=8.2 Hz,1H),3.01 (t, J=7.4 Hz, 2H), 2.94 (t, J=7.4 Hz, 2H), 2.10 (p, J=7.4 Hz,2H).

N-(4-cyano-2,5-difluorophenyl)-1 H-benzo[g]indole-3-sulfonamide I-151

Neutral LCMS Method 3 (ES⁺): 384.05 (M+H)⁺, 96% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 13.06 (s, 1H), 11.22 (s, 1H), 8.41 (dd,J=8.3, 1.2 Hz, 1H), 8.36 (d, J=3.1 Hz, 1H), 8.02-7.95 (m, 2H), 7.82 (dd,J=10.3, 5.9 Hz, 1H), 7.69 (d, J=8.7 Hz, 1 H), 7.60-7.62 (m, 1H),7.55-7.47 (m, 2H).

N-(4-cyano-2-fluorophenyl)-1 H-benzo[g]indole-3-sulfonamide I-152

Neutral LCMS Method 3 (ES⁺): 366.06 (M+H)⁺, 99% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.97 (s, 1H), 10.80 (s, 1H), 8.37-8.39 (m,1H), 8.16 (d, J=3.1 Hz, 1H), 8.00-7.96 (m, 1H), 7.93 (d, J=8.7 Hz, 1H),7.70 (dd, J=10.7, 1.8 Hz, 1H), 7.67-7.58 (m, 3H), 7.57-7.46 (m, 2H).

6-(benzyloxy)-N-(4-cyano-2,5-difluorophenyI)-1H-indole-3-sulfonamideI-153

Neutral LCMS Method 3 (ES⁺): 440.08 (M+H)⁺, 98% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 11.95 (s, 1H), 11.13 (s, 1H), 8.12 (d, J=3.0Hz, 1H), 7.84 (dd, J=10.2, 5.9 Hz, 1 H), 7.75 (d, J=8.8 Hz, 1H),7.47-7.41 (m, 3H), 7.39 (t, J=7.6 Hz, 2H), 7.34-7.30 (m, 1H), 7.02 (d,J=2.2 Hz, 1H), 6.95 (dd, J=8.8, 2.3 Hz, 1H), 5.12 (s, 2H).

6-(benzyloxy)-N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide I-154

Neutral LCMS Method 3 (ES⁺): 422.08 (M+H)⁺, 97% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 11.86 (s, 1H), 10.70 (s, 1H), 7.94 (d, J=2.9Hz, 1H), 7.74-7.69 (m, 2H), 7.60-7.52 (m, 2H), 7.47-7.43 (m, 2H),7.41-7.37 (m, 2H), 7.35-7.29 (m, 1H), 7.02 (d, J=2.2 Hz, 1H), 6.93 (dd,J=8.8, 2.3 Hz, 1H), 5.12 (s, 2H).

N-(2,1,3-benzothiadiazol-4-yl)-1H-benzo[g]indole-3-sulfonamide I-155

Neutral LCMS Method 3 (ES⁺): 381.04 (M+H)⁺, 95.2% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.88 (s, 1H), 10.80 (s, 1H), 8.36 (dq,J=8.3, 0.9 Hz, 1H), 8.18 (d, J=3.0 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.93(dt, J=8.4, 0.8 Hz, 1H), 7.66 (dd, J=8.7, 1.1 Hz, 1 H), 7.55 (m, 3H),7.54 (dd, J=7.4, 1.1 Hz, 1H), 7.46-7.48 (m, 1H).

N-(2,1,3-benzothiadiazol-4-yl)-6-(benzyloxy)-1H-indole-3-sulfonamideI-156

Neutral LCMS Method 3 (ES⁺): 437.07 (M+H)⁺, 99% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 11.78 (s, 1H), 10.70 (s, 1H), 7.97 (d, J=2.9Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.66 (dd, J=8.7, 0.9 Hz, 1H), 7.57 (dd,J=8.8, 7.4 Hz, 1H),7.47 (dd, J=7.5, 1.0 Hz, 1H), 7.44 ? 7.40 (m, 2H),7.37 (t, J=7.6 Hz, 2H), 7.33-7.28 (m, 1H), 6.96 (d, J=2.2 Hz, 1H), 6.85(dd, J=8.8, 2.3 Hz, 1H), 5.08 (s, 2H).

N-(2,1,3-benzothiadiazol-5-yl)-1H-benzo[g]indole-3-sulfonamide I-157

Neutral LCMS Method 3 (ES⁺): 381.04 (M+H)⁺, 97% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.95 (s, 1H), 10.96 (s, 1H), 8.36 (dd,J=8.3, 1.2 Hz, 1H), 8.31 (d, J=2.8 Hz, 1H), 7.99 (d, J=8.8 Hz, 1 H),7.97-7.94 (m, 1H), 7.90 (dd, J =9.4, 0.7 Hz, 1 H), 7.69-7.64 (m, 2H),7.56-7.58 (m, 1 H), 7.53 (dd, J=9.4, 2.2 Hz, 1H), 7.46-7.48 (m, 1 H).

N-(2,1,3-benzothiadiazol-5-yl)-1,6,7,8-tetrahydrocyclopenta[g]indole-3-sulfonamideI-158

Neutral LCMS Method 3 (ES⁺): 371.05 (M-FH)+, 100% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.02 (s, 1H), 10.85 (s, 1H), 8.14 (d, J=3.0Hz, 1H), 7.89 (dd, J=9.4, 0.7 Hz, 1 H), 7.69-7.65 (m, 1 H), 7.59 (dd,J=2.2, 0.7 Hz, 1H), 7.50 (dd, J=9.4, 2.2 Hz, 1H), 7.09 (d, J=8.1 Hz,1H), 2.97 (t, J=7.4 Hz, 2H), 2.90 (t, J=7.4 Hz, 2H), 2.11-2.00 (m, 2H).

N-(4-cyanophenyI)-1H-benzo[g]indole-3-sulfonamide I-159

Neutral LCMS Method 3 (ES⁺): 348.07 (M+H)⁺, 98% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.96 (s, 1H), 10.97 (s, 1H), 8.39 (dd,J=8.3, 1.2 Hz, 1H), 8.22 (d, J=2.9 Hz, 1H), 7.95 (dd, J=19.9, 8.5 Hz,2H), 7.67 (d, J=8.8 Hz, 1H),7.64-7.57 (m, 3H), 7.50- 7.52 (m, 1 H), 7.32? 7.25 (m, 2H).

N-(6-fluoro-2,1,3-benzothiadiazol-5-yl)-1H-benzo[g]indole-3-sulfonamideI-160

Neutral LCMS Method 3 (ES⁺): 399.03 (M+H)⁺, 97% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.97 (s, 1H), 10.79 (s, 1H), 8.37-8.39 (m,1H), 8.27 (d, J=3.1 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.98-7.94 (m, 1H),7.90 (d, J=7.8 Hz, 1H), 7.86 (d, J=10.8 Hz, 1H), 7.68-7.64 (m, 1H),7.57-7.59 (m, 1H), 7.48-7.51(m, 1H).

N-(2,1,3-benzoselenadiazol-5-yl)-6-chloro-1H-indole-3-sulfonamide I-161

Neutral LCMS Method 3 (ES⁺): 412.93 (M+H)⁺, 98% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.14 (s, 1H), 10.81 (s, 1H), 8.22 (s, 1H),7.88 (d, J=8.6 Hz, 1H), 7.67 (d, J=10.3 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H),7.39-7.33 (m, 2H), 7.25 (dd,

J=8.6, 1.9 Hz, 1H).

6-chloro-N-(6-fluoro-2,1,3-benzothiadiazol-5-yl)-1H-indole-3-sulfonamideI-162

Neutral LCMS Method 3 (ES⁺): 383.09 (M-FH)+, 97% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.16 (s, 1H), 10.76 (s, 1H), 8.22 (s, 1H),7.80-7.92 (m, 3H), 7.51 (s, 1H), 7.18-7.28 (m, 1H).

6-chloro-N-(7-cyano-2,1,3-benzothiadiazol-4-yl)-1H-indole-3-sulfonamideI-163

Neutral LCMS Method 3 (ES⁺): 390.3 (M+H)⁺, 95% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 11.52 (s, 1 H), 7.74-7.85 (m, 1 H), 7.68 (d,J=8.5 Hz, 1H), 7.24-7.45 (m, 2H), 7.04-7.11 (m, 1H), 6.94 (d, J=8.4 Hz,1H).

N-(4-cyano-2,5-difluorophenyI)-4,6-difluoro-1H-indole-3-sulfonamideI-164

Neutral LCMS Method 3 (ES⁺): 369.2 (M+H)⁺, 95% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.47 (s, 1H), 11.04 (s, 1 H), 8.25 (d,J=3.0 Hz, 1H), 7.85 (dd, J=10.1, 5.8 Hz, 1H), 7.43 (dd, J=10.9, 6.2 Hz,1H), 7.16 (dd, J=8.7, 2.1 Hz, 1H), 7.05 (td, J=10.5, 2.2 Hz, 1H).

N-(4-cyano-2,5-difluorophenyI)-6-fluoro-1H-indole-3-sulfonamide I-165

Neutral LCMS Method 3 (ES⁺): 351.3 (M+H)⁺, 98% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.28-12.11 (m, 1 H), 11.18 (s, 1H), 8.26(d, J=3.0 Hz, 1H), 7.84 (ddd, J=14.4, 9.5, 5.6 Hz, 2H), 7.43 (dd,J=11.0, 6.4 Hz, 1H), 7.27 (dd, J=9.5, 2.4 Hz, 1H), 7.10 (td, J=9.3, 2.4Hz, 1H).

N-(2,1,3-benzothiadiazol-4-yl)-4,6-difluoro-1H-indole-3-sulfonamideI-166

Neutral LCMS Method 3 (ES⁺): 366.3 (M+H)⁺, 99% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.26 (s, 1H), 10.16 (s, 1H), 8.07 (s, 1H),7.70 (dd, J=8.9, 0.9 Hz, 1H), 7.58 (dd, J=8.8, 7.4 Hz, 1H), 7.47 (dd,J=7.4, 0.9 Hz, 1H), 7.08 (dd, J =9.0, 2.1 Hz, 1H), 6.96 (td, J=10.4, 2.2Hz, 1H).

7-bromo-N-(4-cyano-2,5-difluorophenyI)-1H-indole-3-sulfonamide I-167

Neutral LCMS Method 3 (ES⁺): 412.2 (M+H)⁺, 99% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.75-12.27 (m, 1H), 11.22 (s, 1H), 8.30 (d,J=3.1 Hz, 1H), 8.01-7.72 (m, 2H), 7.55-7.38 (m, 2H), 7.17 (t, J=7.8 Hz,1H).

N-(4-cyano-2-fluorophenyl)-4,6-difluoro-1H-indole-3-sulfonamide I-168

Neutral LCMS Method 3 (ES⁺): 351.3 (M+H)⁺, 98% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.36 (s, 1H), 10.56 (s, 1H), 8.08 (d, J=2.5Hz, 1H), 7.80-7.68 (m, 1H), 7.59-7.49 (m, 2H), 7.15 (dd, J=9.0, 2.1 Hz,1H), 7.03 (m, J=10.8, 10.1, 2.1 Hz, 1H).

N-(2,1,3-benzothiadiazol-5-yl)-6-fluoro-1H-indole-3-sulfonamide I-169

Neutral LCMS Method 3 (ES⁺): 348.3 (M+H)⁺, 97% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.08 (s, 1H), 10.91 (s, 1H), 8.20 (dd,J=7.1, 2.4 Hz, 1H), 7.91 (dd, J=9.4, 0.7 Hz, 1H), 7.86 (dd, J=8.8, 5.3Hz, 1H), 7.59 (dd, J=2.2, 0.7 Hz, 1H), 7.48 (dd, J=9.4, 2.2 Hz, 1H),7.22 (m, J=9.6, 2.4, 0.5 Hz, 1H), 7.08 (m, J=9.7, 8.8, 2.4 Hz, 1H).

N-(4-cyano-2-fluorophenyl)-6-(propan-2-yl)-1H-indole-3-sulfonamide I-170

Neutral LCMS Method 3 (ES⁺): 357.4 (M+H)⁺, 95% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 11.93 (d, J=3.0 Hz, 1H), 10.74 (s, 1H), 8.02(d, J=3.0 Hz, 1H), 7.84-7.68 (m, 2H), 7.61-7.44 (m, 2H), 7.27 (t, J=0.9Hz, 1H), 7.10 (dd, J=8.3, 1.5 Hz, 1H), 2.96 (d, J=6.9 Hz, 1H), 1.21 (d,J=6.9 Hz, 7H).

N-(4-cyanophenyl)-6-fluoro-1 H-indole-3-sulfonamide I-171

Neutral LCMS Method 3 (ES⁺): 315.32 (M+H)⁺, 97% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.12 (s, 1H), 10.95 (s, 1H), 8.39-8.06 (m,1H), 7.80 (dd, J=8.8, 5.2 Hz, 1 H), 7.68-7.56 (m, 2H), 7.34-7.14 (m,3H), 7.08 (m, J=9.6, 8.8, 2.4 Hz, 1H).

6-fluoro-N-(6-fluoro-2,1,3-benzothiadiazol-5-yl)-1H-indole-3-sulfonamideI-172

Neutral LCMS Method 3 (ES⁺): 366.3 (M+H)⁺, 99% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.11 (d, J=3.2 Hz, 1H), 10.76 (s, 1H), 8.19(d, J=3.0 Hz, 1 H), 8.04-7.69 (m, 3H), 7.24 (dd, J=9.5, 2.4 Hz, 1 H),7.08 (m, J=9.7, 8.8, 2.4 Hz, 1 H).

N-(4-bromo-2-fluorophenyl)-6-methyl-1 H-indole-3-sulfonamide I-173

Neutral LCMS Method 3 (ES⁺): 383.2 (M+H)⁺, 95% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 11.81 (d, J=3.1 Hz, 1H), 10.01 (s, 1H), 7.77(d, J=3.0 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.40 (dd, J=9.9, 2.1 Hz, 1H),7.32-7.14 (m, 3H), 6.98 (dd, J=8.3, 1.5 Hz, 1H), 2.38 (s, 3H).

N-(4-chloro-2-fluorophenyl)-6-methyl-1H-indole-3-sulfonamide I-174

Neutral LCMS Method 3 (ES⁺): 338.7 (M+H)⁺, 95% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 11.81 (d, J=3.0 Hz, 1H), 9.99 (s, 1H), 7.77(d, J=2.9 Hz, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.34-7.22 (m, 3H), 7.14 (m,J=8.7, 2.4, 1.1 Hz, 1H), 6.98 (dd, J=8.1, 1.4 Hz, 1H), 2.38 (s, 3H).

N-(4-chloro-5-fluoro-2-methoxyphenyl)-1 H-benzo[g]indole-3-sulfonamideI-175

Neutral LCMS Method 3 (ES⁺): 404.8 (M+H)⁺, 95% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.85 (d, J=3.3 Hz, 1H), 9.63 (s, 1H), 8.38(d, J=8.2 Hz, 1H), 8.03 (d, J=2.8 Hz, 1 H), 7.95 (dd, J=30.6, 8.4 Hz,2H), 7.70-7.57 (m, 2H), 7.49 (m, J=8.1, 6.8, 1.2 Hz, 1H), 7.31 (d,J=10.6 Hz, 1H), 7.01 (d, J=6.9 Hz, 1H), 3.37 (s, 3H).

6-chloro-N-(4-cyano-2,5-difluorophenyI)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamideI-176

Neutral LCMS Method 3 (ES⁺): 369.2 (M+H)⁺, 98% purity.

¹H NMR (500 MHz, DMSO-d₆) 612.97 (br, 1H, NH), 11.20 (br, 1H, NH), 8.46(d, J=3.0 Hz, 1H), 8.28 (d, J=8.3 Hz, 1H), 7.86 (dd, J=10.3, 6.0 Hz,1H), 7.47 (dd, J=10.8, 6.4

Hz, 1H), 7.40 (d, J=8.2 Hz, 1H).

6-bromo-N-(4-cyano-2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamideI-177

Neutral LCMS Method 3 (ES⁺): 395.2 (M+H)⁺, 99% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.91 (br, 1H, NH), 10.81 (br, 1H, NH), 8.24(s, 1H), 8.13 (d, J=8.3 Hz, 1H), 7.70-7.76 (m, 1H), 7.52-7.58 (m, 2H),7.48 (d, J=8.3 Hz, 1H).

6-chloro-N-(4-cyanophenyI)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide I-178

Neutral LCMS Method 3 (ES⁺): 333.1 (M+H)⁺, 97% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.90 (br, 1H, NH), 11.00 (br, 1H, NH), 8.33(s, 1H), 8.20 (d, J=8.3 Hz, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.4Hz, 1H), 7.23 (d, J=8.9 Hz, 2H).

N-(2,1,3-benzothiadiazol-5-yl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonamideI-179

Neutral LCMS Method 3 (ES⁺): 366.0 (M+H)⁺, 96% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.87 (br, 1H, NH), 10.97 (br, 1H, NH), 8.41(s, 1H), 8.26 (d, J=8.4 Hz, 1H), 7.92 (dd, J=9.4, 0.7 Hz, 1H), 7.61 (dd,J=2.2, 0.6 Hz, 1H), 7.47 (dd, J=9.4, 2.2 Hz, 1H), 7.37 (d, J=8.3 Hz,1H).

6-chloro-N-1⁻4-(cyanomethyl)phenyl1-1H-indole-3-sulfonamide I-180

Neutral LCMS Method 3 (ES⁺): 346.2 (M+H)⁺, 98% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 12.03 (br, 1H), 10.24 (br, 1H), 7.79 (dd,J=8.6, 0.5 Hz, 1H), 7.48 (dd, J=1.9, 0.5 Hz, 1H), 7.20 (dd, J=10.5, 8.7Hz, 2H), 7.15-7.11 (m, 7H), 7.10-7.06 (m, 3H), 3.84 (s, 2H) ppm.

6-chloro-N-(3-chloro-4-cyanophenyl)-1 H-indole-3-sulfonamide I-181

Neutral LCMS Method 3 (ES⁺): 383.0 (M+NH4)+, 98% purity.

6-chloro-N-(4-cyano-2,6-difluorophenyI)-1H-indole-3-sulfonamide I-182

Neutral LCMS Method 3 (ES⁺): 385.2 (M+H)⁺, 92% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 12.09 (br, 1H), 10.10 (br, 1H), 7.87 (d,J=3.0 Hz, 1H), 7.78-7.72 (m, 2H), 7.60 (d, J=8.5 Hz, 1H), 7.54 (dd,J=1.9, 0.6 Hz, 1H), 7.19 (dd, J=8.6, 1.9 Hz, 1H).

N-(2,1,3-benzothiadiazol-5-yl)-6-bromo-1H-indole-3-sulfonamide I-183

Neutral LCMS Method 3 (ES⁺): 411.2 (M+H)⁺, 97% purity.

¹H NMR (600 MHz, DMSO-d₆) δ: 12.47 (d, J=3.2 Hz, 1H), 10.86 (s, 1H),8.30 (d, J=3.4 Hz, 1H), 8.04 (d, J=8.4 Hz, 1 H), 7.82 (s, 1 H),7.75-7.68 (m, 1 H), 7.55-7.58 (m, 2H), 7.52 (d, J=8.6 Hz, 1H).

N-(4-cyano-2,5-difluorophenyl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide I-184

Neutral LCMS Method 3 (ES⁺): 402.0 (M+H)⁺, 99% purity.

¹H NMR (600 MHz, DMSO-d₆) δ: 12.55 (d, J=3.2 Hz, 1H), 11.26 (s, 1H),8.48 (d, J=3.2 Hz, 1H), 8.07 (d, J=8.4 Hz, 1 H), 7.88-7.84 (m, 1H), 7.83(s, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.46 (dd, J=10.9, 6.3 Hz, 1H).

6-chloro-N-(4-cyano-2,5-difluorophenyI)-1H-indole-3-sulfonamide I-185

Neutral LCMS Method 3 (ES⁺): 385.1 (M+NH4)+, 98% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 12.26 (d, J=3.0 Hz, 1H), 11.17 (s, 1H),8.29 (d, J=3.0 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.84 (dd, J=11.1, 6.0Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.44 (dd, J=11.0, 6.4 Hz, 1H), 7.26(dd, J=8.6, 1.9 Hz, 1H).

N-(2,1,3-benzothiadiazol-4-yl)-6-(trifluoromethyl)-1H-indole-3-sulfonamideI-186

Neutral LCMS Method 3 (ES⁺): 399.1 (M+H)⁺, 92% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 12.35 (s, 1H), 10.87 (s, 1H), 8.31 (d,J=2.7 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.76 (dd, J=1.5, 0.8 Hz, 1H),7.69 (dd, J=8.8, 0.9 Hz, 1 H), 7.58 (dd, J=8.8, 7.4 Hz, 1 H), 7.49 (dd,J=7.4, 0.9 Hz, 1H), 7.43 (dd, J=8.5, 1.6 Hz, 1H).

N-(4-cyano-2,5-difluorophenyl)-6-methyl-1 H-indole-3-sulfonamide I-187

Neutral LCMS Method 3 (ES⁺): 365.1 (M+NH4)+, 96% purity.

6-bromo-N-(4-cyano-2,5-difluorophenyI)-1H-indole-3-sulfonamide I-188

Neutral LCMS Method 3 (ES⁺): 429.2 (M+NH4)+, 98% purity.

¹H NMR (600 MHz, DMSO-d₆) δ: 12.26 (s, 1H), 11.19 (s, 1H), 8.28 (d,J=3.0 Hz, 1H), 7.84 (dd, J=10.3, 5.9 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H),7.67 (s, 1H), 7.43 (dd, J=10.9, 6.3 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H).

N-(4-cyano-2-fluorophenyl)-6-(trifluoromethyl)-1H-indole-3-sulfonamideI-189

Neutral LCMS Method 3 (ES⁺): 401.3 (M+NH₄)+, 95% purity.

¹H NMR (600 MHz, DMSO-d₆) δ:12.46 (d, J=3.4 Hz, 1H), 10.86 (s, 1H), 8.30(d, J=3.0 Hz, 1H), 8.03 (d, J=8.5 Hz, 1 H), 7.82 (s, 1 H), 7.76-7.69 (m,1H), 7.55-7.58 (m, 2H), 7.52 (dd, J=8.6, 1.6 Hz, 1 H).

N-(4-cyanophenyl)-6-(trifluoromethyl)-1 H-indole-3-sulfonamide I-190

Neutral LCMS Method 3 (ES⁺): 383.3 (M+NH₄)+, 98% purity.

¹H NMR (600 MHz, DMSO-d₆) δ:12.46 (s, 1H), 11.04 (s, 1H), 8.37 (s, 1H),8.02 (d, J=8.5 Hz, 1H), 7.81 (s, 1H), 7.62 (d, J=8.7 Hz, 2H), 7.53 (d,J=8.7 Hz, 1H), 7.24 (d, J=8.8 Hz, 2H).

N-(5-chloro-3-fluoropyridin-2-yl)-1H-benzo[g]indole-3-sulfonamide I-191

Neutral LCMS Method 3 (ES⁺): 375.8 (M+H)⁺, 96% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.91 (d, J=3.3 Hz, 1H), 11.06 (s, 1H), 8.40(dd, J=8.2, 1.2 Hz, 1 H), 8.09 (dd, J=31.3, 2.6 Hz, 2H), 8.01-7.86 (m,3H), 7.72-7.54 (m, 2H), 7.49 (m, J=8.1, 6.9, 1.2 Hz, 1H).

N-(2,1,3-benzothiadiazol-5-yl)-6-(trifluoromethyl)-1H-indole-3-sulfonamideI-192

Neutral LCMS Method 3 (ES⁺): 399 (M+H)⁺, 99% purity.

¹H NMR (600 MHz, DMSO-d₆) δ: 12.43 (s, 1H), 11.02 (s, 1H), 8.45 (s, 1H),8.08 (d, J=8.5 Hz, 1H), 7.91 (d, J=9.4 Hz, 1H), 7.78 (s, 1H), 7.61 (d,J=2.5 Hz, 1H), 7.53 (dd, J=8.5, 1.6 Hz, 1H), 7.48 (dd, J =9.4, 2.2 Hz,1H).

6-bromo-N-(6-fluoro-2,1,3-benzothiadiazol-5-yl)-1H-indole-3-sulfonamideI-193

Neutral LCMS Method 3 (ES⁺): 429.1 (M+H)⁺, 99% purity.

6-chloro-N[5-(cyanomethyl)-3-methoxypyridin-2-yl]-1H-indole-3-sulfonamideI-194

Basic LC-MS Method 2 (ES⁺): 377 (M+H)⁺, 100% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 3.76 (s, 3H) 3.90 (s, 2H) 7.20-7.28 (m, 2H)7.50 (d, J=1.47 Hz, 1H) 7.66 (s, 1H) 7.95 (d, J=8.31 Hz, 1H) 8.10 (s,1H) 10.11 (brs, 1H) 12.03 (brs, 1H).

6-chloro-N-[4-chloro-5-(difluoromethoxy)-2-fluorophenyl]-1H-indole-3-sulfonamide I-195

Basic LC-MS Method 2 (ES⁻): 423 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.12 (t, J=72 Hz, 1H) 7.21 (dd, J=8.8, 2.0Hz, 1H) 7.28 -7.33 (m, 1H) 7.50-7.55 (m, 2H) 7.75 (d, J=8.8 Hz, 1H) 7.94(d, J=2.45 Hz, 1H) 10.41 (brs, 1H) 12.12 (brs, 1H).

6-chloro-7-methoxy-N-(2,4,5-trifluorophenyl)-1 H-indole-3-sulfonamideI-196

Basic LC-MS Method 2 (ES⁻): 389 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.89 (s, 3H) 7.20 (d, J=8.00 Hz, 1H)7.29-7.36 (m, 1H) 7.42-7.49 (m, 2H) 7.92 (d, J=2.40 Hz, 1H) 10.22 (s,1H) 12.47 (s, 1H).

6-chloro-N-(7-fluoro-2,1,3-benzoxadiazol-4-yl)-1H-indole-3-sulfonamideI-197

Basic LC-MS Method 2 (ES⁻): 365 (M−H)⁻, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.13-7.17 (m, 1H) 7.21 (d, J=8.8 Hz, 1H)7.30-7.34 (m, 1H) 7.50 (s, 1H) 7.83 (d, J=9.2 Hz, 1H) 8.2 (d, J=2.8 Hz,1H) 11.15 (brs, 1H) 12.16 (brs, 1H).

6-chloro-N-(4-chloro-2,5-difluorophenyI)-1-benzofuran-3-sulfonamideI-198

Basic LC-MS Method 2 (ES⁻): 376 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.38-7.44 (m, 1H) 7.51 (d, J=8.40 Hz, 1H)7.60 (t,

J=8.40 Hz, 1 H) 7.78 (d, J=8.00 Hz, 1 H) 7.97 (s, 1 H) 8.74 (s, 1H)10.99 (s, 1 H).

6-chloro-N-(5-chloro-3,6-difluoropyridin-2-yI)-1H-indole-3-sulfonamideI-199

Basic LC-MS Method 2 (ES⁺): 378 (M-FH)+, 96% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.26 (dd, J=8.80, 1.47 Hz, 1H) 7.55 (d,J=1.47 Hz, 1H) 7.88 (d, J=8.31 Hz, 1H) 8.15 (d, J=2.93 Hz, 1H) 8.21 (t,J=7.83 Hz, 1H) 11.49 (brs, 1H) 12.22 (brs, 1H).

6-chloro-N-(3,6-difluoropyridin-2-yl)-1H-indole-3-sulfonamide I-200

Basic LC-MS Method 2 (ES⁻): 344 (M−H)⁻, 93% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.75 (d, J=8.31 Hz, 1H) 7.24 (dd, J=8.5,1.71 Hz, 1H) 7.54 (d, J=1.5 Hz, 1H) 7.75-7.83 (m, 1H) 7.88 (d, J=8.3 Hz,1H) 8.13 (d, J=2.9 Hz, 1H) 11.25 (brs, 1H) 12.18 (brs, 1H).

6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-fluoro-1H-indole-3-sulfonamideI-242

Basic LC-MS Method 2 (ES⁻): 393 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.26-7.39 (m, 2H) 7.51-7.62 (m, 2H) 8.13 (s,J=2.45 Hz, 1H) 10.55 (s, 1H) 12.90 (brs, 1H).

6-chloro-N-(6-fluoro-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-1H-indole-3-sulfonamideI-243

Basic LC-MS Method 2 (ES⁻F): 381 (M-FH)+, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 5.28 (s, 2H) 7.23 (dd, J=8.56, 1.71 Hz, 1H)7.46 (d, J=9.29 Hz, 1 H) 7.52 (d, J=1.96 Hz, 1H) 7.67 (d, J=6.85 Hz, 1H) 7.77 (d, J=8.80 Hz, 1H) 7.97 (d, J=2.93 Hz, 1H) 10.44 (s, 1H) 12.11(brs, 1H).

6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-methoxy-1H-indole-3-sulfonamide I-244

Basic LC-MS Method 2 (ES⁻): 405 (M−H)⁻, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.90 (s, 3H) 7.24 (d, J=8.31 Hz, 1H)7.34-7.40 (m, 1H) 7.52-7.59 (m, 2H) 8.06 (d, J=2.93 Hz, 1H) 10.52 (s,1H) 12.54 (brs, 1H).

N-(5-bromo-3,6-difluoropyridin-2-yI)-6-chloro-1H-indole-3-sulfonamideI-245

Basic LC-MS Method 2 (ES⁺): 422 (M+H)⁺, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.24 (d, J=7.82 Hz, 1H) 7.54 (s, 1H) 7.87(d, J=8.31 Hz, 1H) 8.13 (s, 1H) 8.21-8.28 (m, 1H) 11.48 (brs, 1H) 12.18(brs, 1H).

6-chloro-N-[4-(2,2-difluoroethoxy)-2,5-difluorophenyl]-1H-indole-3-sulfonamide I-246

Basic LC-MS Method 2 (ES⁻): 421 (M−H)⁻, 95% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 4.26-4.36 (m, 2H) 6.35 (t, J=54 Hz, 1H)7.02-7.18 (m, 2H) 7.20 (dd, J=8.56, 1.71 Hz, 1 H) 7.51 (d, J=1.47 Hz,1H) 7.69 (d, J=8.31 Hz, 1H) 7.86 (d, J=2.45 Hz, 1H) 9.94 (s, 1H) 12.04(brs, 1H).

N-(4-chloro-2,5-difluorophenyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide1-247

Basic LC-MS Method 2 (ES⁻): 410 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.34-7.39 (m, 1H) 7.48-7.54 (m, 1H) 7.79 (d,J=8.31 Hz, 1H) 8.41 (d, J=8.31Hz, 1H) 8.46 (s, 1H) 10.60 (s, 1H) 13.18(brs, 1H).

5-bromo-6-chloro-N-(4-chloro-2,5-difluorophenyl)-1H-indole-3-sulfonamide I-248

Basic LC-MS Method 2 (ES⁻): 455 (M−H)⁻, 95% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.32-7.36 (m, 1H) 7.50-7.56 (m, 1H) 7.73 (s,1H) 8.07-8.13 (m, 2H) 10.50 (s, 1H) 12.29 (brs, 1H).

7-bromo-6-chloro-N-(4-chloro-2,5-difluorophenyl)-1H-indole-3-sulfonamide I-249

Basic LC-MS Method 2 (ES⁻): 455 (M−H)⁻, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.38 (dd, J=10.03, 7.09 Hz, 1H) 7.43 (d,J=8.31 Hz, 1H) 7.53-7.59 (m, 1H) 7.79 (d, J=8.31 Hz, 1H) 8.07 (d, J=2.93Hz, 1H) 10.57 (s, 1H) 12.53 (brs, 1H).

6-bromo-N-(4-chloro-2,5-difluorophenyI)-4-fluoro-1H-indole-3-sulfonamideI-251

Basic LC-MS Method 2 (ES⁺): 439 (M+H)⁺, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.26 (d, J=10.29 Hz, 1H) 7.32-7.39 (m, 1H)7.52 (d, J=1.25 Hz, 1H) 7.56 (m, 1H) 8.06 (s, 1H) 10.27 (s, 1H) 12.39(brs, 1H).

6-chloro-N-{3,6-difluoro-5-[(1E)-3-methoxyprop-1-en-1-yl]pyridin-2-yl}-1H-indole-3-sulfonamide 1-252

Basic LC-MS Method 2 (ES⁺): 414 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.26 (s, 3H) 4.01 (brs, 2H) 6.43 (brs, 2H)7.20-7.29 (m, 1H) 7.54 (s, 1H) 7.88 (d, J=8.80 Hz, 1H) 8.08 (t, J=8.80Hz, 1H) 8.13 (brs, 1H) 11.28 (brs, 1H) 12.18 (brs, 1H).

6-chloro-N-[3,6-difluoro-5-(3-methoxypropyl)pyridin-2-yl]-1H-indole-3-sulfonamideI-253

Basic LC-MS Method 2 (ES⁺): 416 (M+H)⁺, 98% purity. ¹H NMR (400 MHz,DMSO-d₆) δ 1.65-1.75 (m, 2H) 3.18 (s, 3H) 3.26 (t, J=6.11 Hz, 2H)7.20-7.27 (m, 1H) 7.54 (d, J=1.96 Hz, 1H) 7.73 (dd, J=9.29, 7.83 Hz, 1H)7.84 (d, J=8.80 Hz, 1H) 8.09 (d, J=2.93 Hz, 1H) 11.00 (s, 1H) 12.15(brs, 1H) (2H′s merged in solvent peak).

6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-1H-indole-3-sulfonamide I-254

Basic LC-MS Method 2 (ES⁺): 390 (M+H)⁺, 95% purity. ¹H NMR (400 MHz,DMSO-d₆) δ 3.63 (s, 3H) 7.23 (dd, J=8.56, 1.71 Hz, 1H) 7.54 (d, J=1.96Hz, 1H) 7.84 (d, J=8.80 Hz, 1H) 7.94 (d, J=8.80 Hz, 1H) 8.16 (d, J=2.93Hz, 1H) 11.11 (s, 1H) 12.11 (brs, 1H).

6-chloro-N[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamideI-255

Basic LC-MS Method 2 (ES⁺): 395 (M+H)⁺, 98% purity. ¹H NMR (400 MHz,DMSO-d₆) δ 3.62 (s, 3H) 3.70 (s, 2H) 7.22 (dd, J=8.80, 1.96 Hz, 1H) 7.54(d, J=1.96 Hz, 1H) 7.62 (d, J=9.78 Hz, 1H) 7.85 (d, J=8.31 Hz, 1H) 8.15(d, J=2.93 Hz, 1H) 11.02 (s, 1H) 12.08 (brs, 1H).

6-chloro-N-[4-(cyanomethoxy)-2,5-difluorophenyI]-1H-indole-3-sulfonamideI-257

Basic LC-MS Method 2 (ES⁻): 396 (M−H)⁻, 98% purity. ¹H NMR (400 MHz,DMSO-d₆) δ 5.18 (s, 2H) 7.14-7.27 (m, 3H) 7.52 (d, J=1.96 Hz, 1H) 7.67(d, J=8.80 Hz, 1H) 7.91 (d, J=2.45 Hz, 1H) 10.05 (s, 1H) 12.07 (brs,1H).

6-chloro-N-(4-cyano-2-fluorophenyI)-5-fluoro-1H-indole-3-sulfonamideI-258

Basic LC-MS Method 2 (ES⁻): 366 (M−H)⁻, 97% purity. ¹H NMR (400 MHz,DMSO-d₆) δ 7.57 (d, J=3.91 Hz, 2H) 7.69 (d, J=6.36 Hz, 1 H) 7.74-7.81(m, 2H) 8.20 (d, J=2.93 Hz, 1H) 10.81 (s, 1H) 12.31 (brs, 1H).

N-(4-bromo-2,5-difluorophenyI)-6-chloro-1-benzofuran-3-sulfonamide I-259

Basic LC-MS Method 2 (ES⁺): 422 (M+H)⁺, 99% purity. ¹H NMR (400 MHz,DMSO-d₆) δ 7.36-7.40 (m, 1H) 7.51 (dd, J=8.56, 1.71 Hz, 1H) 7.62-7.66(m, 1 H) 7.78 (d, J=8.31 Hz, 1H) 7.96 (d, J=1.47 Hz, 1H) 8.76 (s, 1 H)11.00 (brs, 1 H).

6-chloro-N-[4-(cyclopropylmethoxy)-2,5-difluorophenyl]-1H-indole-3-sulfonamide I-260

Basic LC-MS Method 2 (ES⁻): 411 (M−H)⁻, 98% purity. ¹H NMR (400 MHz,DMSO-d₆) δ 0.24-0.31 (m, 2H) 0.50-0.57 (m, 2H) 1.12-1.21 (m, 1H) 3.79(d, J=6.85 Hz, 2H) 6.92-7.05 (m, 2H) 7.20 (dd, J=8.56, 1.71 Hz, 1H) 7.52(d, J=1.47 Hz, 1H) 7.69 (d, J=8.31 Hz, 1H) 7.84 (d, J=1.96 Hz, 1H) 9.83(s, 1H) 12.03 (brs, 1H).

6-chloro-N-(4-chloro-2,5-difluorophenyI)-7-(2,2-difluoroethoxy)-1H-indole-3-sulfonamideI-262

Basic LC-MS Method 2 (ES⁻): 455 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 4.36-4.41 (m, 2H) 6.27-6.59 (m, 1H) 7.26 (d,J=8.68 Hz, 1H) 7.33-7.37 (m, 1H) 7.52-7.56 (m, 1H) 7.58 (d, J=8.68 Hz,1H) 8.12 (d, J=2.81 Hz, 1H) 10.54 (s, 1H) 12.46 (brs, 1H).

6-chloro-N-(4-chloro-2,5-difluorophenyl)-5-fluoro-1H-indole-3-sulfonamideI-263

Basic LC-MS Method 2 (ES⁻): 393 (M−H)⁻, 95% purity. ¹H NMR (400 MHz,DMSO-d₆) δ 7.37 (dd, J=10.51, 7.09 Hz, 1H) 7.56 (dd, J=10.27, 6.85 Hz,1H) 7.68 (d, J=6.36 Hz, 1H) 7.73 (d, J=10.27 Hz, 1H) 8.13 (d, J=2.93 Hz,1H) 10.50 (s, 1H) 12.26 (brs, 1H).

6-chloro-N-(3,5-dimethoxypyridin-2-yl)-1 H-indole-3-sulfonamide I-264

Basic LC-MS Method 2 (ES⁺): 368 (M+H)⁺, 95% purity. ¹H NMR (400 MHz,DMSO-d₆) δ 3.66 (s, 3H) 3.75 (s, 3H) 6.94 (d, J=2.45 Hz, 1H) 7.14-7.24(m, 1 H) 7.46-7.51 (m, 2H) 7.85-7.89 (m, 1 H) 7.95 (s, 1 H) 9.64 (brs,1H) 11.95 (brs, 1H).

6-chloro-N-(6-fluoro-3-oxo-2,3-dihydro-1H-isoindo1-5-yl)-1H-indole-3-sulfonamideI-265

Basic LC-MS Method 2 (ES⁺): 380 (M+H)⁺, 98% purity. ¹H NMR (400 MHz,DMSO-d₆) δ 4.25 (s, 2H) 7.21 (dd, J=8.80, 1.96 Hz, 1H) 7.33 (d, J=9.78Hz, 1H) 7.49-7.53 (m, 2H) 7.77 (d, J=8.80 Hz, 1H) 7.89 (d, J=2.93 Hz,1H) 8.59 (s, 1H) 10.21 (s, 1H) 12.07 (d, J=1.96 Hz, 1H).

N-(4-cyano-5-fluoro-2-methoxyphenyI)-1H-benzo[g]indole-3-sulfonamideI-289

Neutral LCMS Method 3 (ES⁺): 396.4 (M+H)⁺, 95.0% purity. ¹H NMR (600MHz, DMSO-d₆) δ: 12.99 (s, 1H), 10.27 (s, 1H), 8.39 (dd, J=8.3, 1.2 Hz,1H), 8.30 (d, J=3.0 Hz, 1H), 8.12-7.94 (m, 2H), 7.66 (d, J=8.7 Hz, 1H),7.62-7.60 (m, 1H), 7.51-7.49 (m, 1H), 7.40 (d, J=11.2 Hz, 1H), 7.34 (d,J=5.9 Hz, 1H), 3.65 (s, 3H).

N-(5-chloro-3,6-difluoropyridin-2-yl)-1H-benzo[g]indole-3-sulfonamideI-304

Basic LCMS Method 1 (ES⁺): 394 (M+H)⁺, 100% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (s, 1H), 11.48 (s, 1H), 8.42 (dd,J=8.2, 1.0 Hz, 1H), 8.18 (d, J=3.2 Hz, 2H), 8.00 (dd, J=8.5, 6.5 Hz,2H), 7.68 (d, J=8.8 Hz, 1H), 7.57 (dddd, J=54.0, 8.2, 6.9, 1.2 Hz, 2H).

N-(4-bromo-2,5-difluorophenyI)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamideI-305

Basic LCMS Method 1 (ES⁺): 438 (M+H)⁺, 95% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (s, 1H), 10.51 (s, 1H), 8.92 (dd,J=4.4, 1.7 Hz, 1H), 8.44 (dd, J=8.2, 1.7 Hz, 1H), 8.04-7.91 (m, 2H),7.69 (d, J=8.7 Hz, 1 H), 7.57 (dt, J=10.4, 5.2 Hz, 2H), 7.36 (dd,J=10.0, 6.8 Hz, 1H).

N-(4-ethynyl-2-fluorophenyl)-1 H-pyrrolo[3,2-h]quinoline-3-sulfonamideI-306

Basic LCMS Method 1 (ES⁻F): 366 (M+H)⁺, 97% purity.

6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-7-methoxy-1H-indole-3-sulfonamide1-309

Basic LC-MS Method 2 (ES⁺): 420 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.60 (s, 3 H) 3.90 (s, 3 H) 7.19 (d, J=8.80Hz, 1 H) 7.58 (d, J=8.80 Hz, 1 H) 7.81 (brs, 1 H) 8.02 (s, 1 H) 11.12(brs, 1 H) 12.37 (brs, 1 H).

6-chloro-N-(4-cyanophenyl)-1-benzothiophene-3-sulfonamide I-311

Basic LC-MS Method 2 (ES⁻): 347 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.21 (d, J=8.31 Hz, 2H) 7.62 (dd, J=8.80,1.96 Hz, 1 H) 7.66 (d, J=8.80 Hz, 2H) 8.16 (d, J=8.80 Hz, 1H) 8.29 (d,J=1.96 Hz, 1H) 8.78 (s, 1H) 11.40 (s, 1H).

6-chloro-N-(4-chloro-2,5-difluorophenyl)-1-benzothiophene-3-sulfonamideI-312

Basic LC-MS Method 2 (ES⁻): 392 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.34-7.39 (m, 1 H) 7.56-7.63 (m, 2H) 8.15(d, J=8.80 Hz, 1 H) 8.31 (d, J=1.96 Hz, 1 H) 8.58 (s, 1 H) 10.91 (br s,1 H).

6-chloro-N-[4-(cyanomethoxy)-2,5-difluorophenyl]-1-benzothiophene-3-sulfonamideI-313

Basic LC-MS Method 2 (ES⁻): 413 (M−H)⁻, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 5.20 (s, 2 H) 7.17-7.30 (m, 2 H) 7.59 (dd,J=8.80, 1.96 Hz, 1 H) 8.06 (d, J=8.80 Hz, 1 H) 8.31 (d, J=1.96 Hz, 1 H)8.46 (s, 1 H) 10.54 (s, 1 H).

6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-1-benzothiophene-3-sulfonamideI-314

Basic LC-MS Method 2 (ES⁻): 405 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.57 (s, 3 H) 7.61 (d, J=4.40 Hz, 1 H) 8.00(d, J=5.38 Hz, 1 H) 8.20-8.22 (m, 1 H) 8.31 (s, 1 H) 8.77 (s, 1 H) 11.64(br s, 1 H).

6-chloro-N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1-benzothiophene-3-sulfonamideI-315

Basic LC-MS Method 2 (ES⁺): 412 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.56 (s, 3 H) 3.71 (s, 2 H) 7.60 (dd,J=8.80, 1.96 Hz, 1 H) 7.68 (d, J=9.29 Hz, 1 H) 8.23 (d, J=8.31 Hz, 1 H)8.31 (d, J=1.96 Hz, 1 H) 8.77 (s, 1 H) 11.57 (brs, 1 H).

6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-7-fluoro-1H-indole-3-sulfonamide I-319

Basic LC-MS Method 2 (ES⁺): 408 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.62 (s, 3 H) 7.30-7.34 (m, 1 H) 7.67 (d,J=8.80 Hz, 1 H) 7.94 (d, J=8.80 Hz, 1 H) 8.22 (d, J=1.47 Hz, 1 H) 11.19(s, 1 H) 12.85 (br s, 1 H)6-bromo-N[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamideI-320

Basic LC-MS Method 2 (ES⁻): 438 (M−H)⁻, 97% purity. ¹H NMR (400 MHz,DMSO-d₆) δ 3.62 (s, 3 H) 3.70 (s, 2 H) 7.34 (d, J=8.31 Hz, 1 H) 7.62 (d,J=9.78 Hz, 1 H) 7.68 (s, 1 H) 7.80 (d, J=8.31 Hz, 1 H) 8.14 (d, J=2.45Hz, 1 H) 11.03 (s, 1 H) 12.09 (br s, 1 H)7-bromo-6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-1H-indole-3-sulfonamide I-321

Basic LC-MS Method 2 (ES⁺): 468 (M+H)⁺, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.63 (s, 3 H) 7.42 (d, J=8.31 Hz, 1 H) 7.85(d, J=8.31 Hz, 1 H) 7.95 (d, J=8.80 Hz, 1 H) 8.14 (d, J=2.93 Hz, 1 H)11.20 (s, 1 H) 12.48 (br s, 1 H)7-bromo-6-chloro-N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamide1-322

Basic LC-MS Method 2 (ES⁺): 473 (M+H)⁺, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.63 (s, 3 H) 3.70 (s, 2 H) 7.42 (d, J=8.31Hz, 1 H) 7.62 (d, J=9.78 Hz, 1 H) 7.86 (d, J=8.80 Hz, 1 H) 8.13 (br s, 1H) 11.12 (s, 1 H) 12.44 (br s, 1 H)6-bromo-N-[3,6-difluoro-5-(3-methoxypropyl)pyridin-2-yI]-1H-indole-3-sulfonamideI-323

Basic LC-MS Method 2 (ES⁻): 458 (M−H)⁻, 96% purity.

¹H NMR (400 MHz, Methanol-d4) δ 1.72-1.83 (m, 2 H) 2.56 (t, J=7.65 Hz, 2H) 3.15 -3.28 (m, 5 H) 7.31 (dd, J=8.53, 1.76 Hz, 1 H) 7.45 (dd, J=9.54,7.78 Hz, 1 H) 7.64 (d, J=1.76 Hz, 1 H) 7.85 (d, J=8.78 Hz, 1 H) 8.03 (s,1 H).

5-bromo-6-chloro-N45-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-ylF1H-indole-3-sulfonamide1-324

Basic LC-MS Method 2 (ES⁺): 473 (M+H)⁺, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.65 (s, 3 H) 3.71 (s, 2 H) 7.64 (d, J=9.78Hz, 1 H) 7.75 (s, 1 H) 8.21 (d, J=1.96 Hz, 1 H) 8.25 (s, 1 H) 11.03 (brs, 1 H) 12.22 (br s, 1 H).

6-bromo-N-{3,6-difluoro-5-[(1E)-3-methoxyprop-1-en-1-yl]pyridin-2-yl}-1-1H-indole-3-sulfonamide 1-325

Basic LC-MS Method 2 (ES⁺): 458 (M-FH)+, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.25 (s, 3 H) 4.01 (d, J=2.93 Hz, 2 H) 6.41(s, 2 H) 7.34 (d, J=8.80 Hz, 1 H) 7.67 (s, 1 H) 7.83 (d, J=8.80 Hz, 1 H)8.03-8.13 (m, 2 H) 11.29 (br s, 1 H) 12.14 (brs, 1 H)6-bromo-N-(5-chloro-3-fluoropyridin-2-yl)-7-methyl-1H-indole-3-sulfonamideI-326

Basic LC-MS Method 1 (ES⁺): 418 (M+H)⁺, 90% purity.

6-chloro-N-(6-fluoro-1-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-1H-indole-3-sulfonamide1-327

Basic LC-MS Method 2 (ES⁺): 395 (M+H)⁺, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 1.48 (d, J=6.85 Hz, 3H) 5.54-5.61 (m, 1H)7.22 (dd, J=8.80, 1.96 Hz, 1H) 7.51-7.55 (m, 2H) 7.65 (d, J=6.85 Hz, 1H)7.73 (d, J=8.80 Hz, 1H) 7.99 (d, J=2.93 Hz, 1H) 10.43 (s, 1H) 12.12(brs, 1H).

N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamideI-328

Basic LC-MS Method 1 (ES⁻): 405 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 13.21 (s, 1H), 11.17 (s, 1H), 8.93 (dd,J=4.4, 1.6 Hz, 1H), 8.45 (dd, J=8.3, 1.6 Hz, 1H), 8.14-8.02 (m, 2H),7.93 (d, J=8.5 Hz, 1H), 7.71 (d, J =8.7 Hz, 1H), 7.58 (dd, J=8.2, 4.4Hz, 1H), 3.64 (s, 3H).

N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-1H-benzo[g]indole-3-sulfonamideI-329

Basic LC-MS Method 1 (ES⁻F): 406 (M-FH)+, 96% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.95 (s, 1H), 11.13 (s, 1H), 8.43 (d, J=8.3Hz, 1H), 8.21 (s, 1 H), 8.07-7.79 (m, 3H), 7.74-7.36 (m, 3H), 3.67 (s,3H).

6-nitro-N-(4-cyano-2-fluorophenyl)-1 H-indole-3-sulfonamide I-334

Basic LC-MS Method 2 (ES⁻): 359 (M−H)⁻, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.58 (brs, 2H) 7.76 (d, J=10.27 Hz, 1H)7.95-8.03 (m, 1H) 8.06-8.15 (m, 1H) 8.38-8.44 (m, 2H) 10.94 (brs, 1H)12.73 (brs, 1H).

6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-5-fluoro-1H-indole-3-sulfonamide I-339

Basic LC-MS Method 2 (ES⁻): 406 (M−H)⁻, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.64 (s, 3 H) 7.69 (d, J=6.36 Hz, 1 H) 7.78(d, J=9.78 Hz, 1 H) 7.94 (d, J=8.80 Hz, 1 H) 8.21 (d, J=2.93 Hz, 1 H)11.07 (s, 1 H) 12.19 (br s, 1 H)6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yI)-5,7-difluoro-1H-indole-3-sulfonamide1-340

Basic LC-MS Method 2 (ES⁺): 426 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.65 (s, 3 H) 7.70 (d, J=9.78 Hz, 1 H) 7.97(d, J=9.29 Hz, 1 H) 8.33 (d, J=1.96 Hz, 1 H) 11.17 (s, 1 H) 13.00 (br s,1 H) 7-bromo-6-chloro-N-(4-cyano-2-fluorophenyI)-1H-indole-3-sulfonamideI-341

Basic LC-MS Method 2 (ES⁻): 426 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.44 (d, J=8.37 Hz, 1 H) 7.56-7.60 (m, 2 H)7.74-7.79 (m, 1 H) 7.84 (d, J=8.37 Hz, 1 H) 8.14 (d, J=2.95 Hz, 1 H)10.89 (br s, 1 H) 12.58 (d, J=1.97 Hz, 1 H).

6-chloro-N-[4-(cyanomethoxy)-2,5-difluorophenyI]-1-benzofuran-3-sulfonamideI-342

Basic LC-MS Method 2 (ES⁻): 397 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 5.21 (s, 2H) 7.26-7.33 (m, 2H) 7.49 (dd,J=8.31, 1.47 Hz, 1H) 7.67 (d, J=8.31 Hz, 1H) 7.97 (d, J=1.47 Hz, 1 H)8.66 (s, 1H) 10.63 (s, 1H).

5-bromo-6-chloro-N-(4-cyano-2-fluorophenyI)-1H-indole-3-sulfonamideI-343

Basic LC-MS Method 2 (ES⁻): 426 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.55-7.60 (m, 2 H) 7.71-7.83 (m, 2 H)8.17-8.21 (m, 2 H) 10.82 (s, 1 H) 12.35 (br s, 1 H).

6-chloro-N-[3-methoxy-5-(trifluoromethyppyridin-2-yl]-1H-indole-3-sulfonamideI-344

Basic LC-MS Method 2 (ES⁺): 406 (M+H)⁺, 96% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.87 (s, 3H) 7.23 (d, J=8.31 Hz, 1 H) 7.51(s, 2H) 7.98 (d, J=8.31 Hz, 1H) 8.06 (s, 1H) 8.18 (s, 1H) 10.67 (brs,1H) 12.13 (brs, 1H).

6-chloro-N-(3,5-difluoro-6-methoxypyridin-2-yl)-1 H-indole-3-sulfonamideI-345

Basic LC-MS Method 2 (ES⁺): 374 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.55 (s, 3 H) 7.19 (dd, J=8.80, 1.96 Hz, 1H) 7.51 (d, J=1.96 Hz, 1 H) 7.76 (d, J=8.31 Hz, 1 H) 7.86 (t, J=9.29 Hz,1 H) 8.06 (d, J=2.93 Hz, 1 H) 10.73 (s, 1 H) 12.05 (brs, 1 H).

6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yI)-1-benzofuran-3-sulfonamideI-346

Basic LC-MS Method 2 (ES⁻): 389 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.59 (s, 3 H) 7.52 (dd, J=8.56, 1.71 Hz, 1H) 7.89 (d, J=8.31 Hz, 1 H) 7.99 (d, J=1.47 Hz, 1 H) 8.03 (d, J=8.80 Hz,1 H) 8.91 (s, 1 H) 11.66 (br s, 1 H).

6-bromo-7-chloro-N-(4-chloro-2,5-difluorophenyl)-1H-indole-3-sulfonamide I-347

Basic LC-MS Method 2 (ES⁺): 455 (M-FH)+, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.36-7.40(m, 1 H) 7.53-7.58 (m, 2H) 7.69 (d,J=8.8 Hz, 1

H) 8.09 (d, J=3.2 Hz, 1 H) 10.57 (s, 1 H), 12.69 (brs, 1H).

6-chloro-N-(3,6-difluoro-5-methylpyridin-2-yI)-1H-indole-3-sulfonamideI-348

Basic LC-MS Method 2 (ES⁺): 358 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 2.08 (s, 3H) 7.22 (dd, J=8.56, 1.71 Hz, 1H)7.53 (d,

J=1.96 Hz, 1 H) 7.72 (t, J=8.80 Hz, 1 H) 7.84 (d, J=8.31 Hz, 1H) 8.08(d, J=2.93 Hz, 1H) 10.98 (s, 1H) 12.13 (brs, 1H).

N-(5-bromo-6-fluoro-3-methoxypyridin-2-yI)-6-chloro-1H-indole-3-sulfonamideI-349

Basic LC-MS Method 2 (ES⁺): 434 (M+H)⁺, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.78 (s, 3H) 7.22 (d, J=8.8 Hz, 1H) 7.53 (s,1H) 7.73 (d, J=7.2 Hz, 1H) 7.94 (d, J=8.8 Hz, 1H) 8.11 (d, J=3.2 Hz, 1H)10.65 (s, 1H), 12.13 (brs, 1H).

6-chloro-N[5-(cyanomethyl)-6-fluoro-3-methoxypyridin-2-yl]-1H-indole-3-sulfonamideI-350

Basic LC-MS Method 2 (ES⁺): 395 (M+H)⁺, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.76 (s, 3H) 3.87 (s, 2H) 7.21 (dd, J=8.80Hz, 0.80 Hz, 1H) 7.47 (d, J=8.40 Hz, 1H) 7.52 (d, J=0.80 Hz, 1H) 7.95(d, J=8.80 Hz, 1H) 8.10 (d, J=2.80 Hz, 1H) 10.55 (s, 1H), 12.12 (brs,1H).

N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-6-nitro-1H-indole-3-sulfonamideI-351

Basic LC-MS Method 2 (ES⁺): 406 (M+H)⁺, 88% purity. ¹H NMR (400 MHz,DMSO-d₆) δ 3.60 (s, 3H) 3.70 (s, 2H) 7.64 (d, J=9.78 Hz, 1H) 8.02-8.06(m, 1H) 8.07-8.11 (m, 1H) 8.42 (d, J=1.96 Hz, 1H) 8.50 (s, 1H) 11.20 (s,1H) 12.62 (brs, 1H).

6-chloro-N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-7-fluoro-1H-indole-3-sulfonamide1-354

Basic LC-MS Method 2 (ES⁺): 413 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.56 (s, 3 H) 3.61 (s, 2 H) 7.23-7.27 (m, 1H) 7.55 (d, J=9.84 Hz, 1 H) 7.59 (d, J=8.86 Hz, 1 H) 8.12 (s, 1 H) 11.13(br s, 1 H) 12.85 (br s, 1 H)6-chloro-N-(3,6-difluoro-5-methylpyridin-2-yl)-7-fluoro-1H-indole-3-sulfonamide I-355

Basic LC-MS Method 2 (ES⁺): 376 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 2.09 (s, 3 H) 7.32 (dd, J=8.56, 6.60 Hz, 1H) 7.67 (d,

J=8.80 Hz, 1 H) 7.71-7.77 (m, 1 H) 8.13 (s, 1 H) 11.07 (br s, 1 H) 12.87(br s, 1 H)7-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yI)-6-methoxy-1H-indole-3-sulfonamide1-356

Basic LC-MS Method 2 (ES⁻): 418 (M−H)⁻, 96% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.62 (s, 3 H) 3.85 (s, 3 H) 7.09 (d, J=8.80Hz, 1 H) 7.73 (d, J=8.80 Hz, 1 H) 7.88 (d, J=9.29 Hz, 1 H) 7.95 (s, 1 H)11.12 (br s, 1 H) 12.14 (br s, 1 H)7-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-6-fluoro-1H-indole-3-sulfonamide I-357

Basic LC-MS Method 2 (ES⁻): 406 (M−H)⁻, 95% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.61 (s, 3 H) 7.25 (t, J=9.54 Hz, 1 H) 7.79(dd, J=8.80, 4.40 Hz, 1 H) 7.91 (d, J=8.80 Hz, 1 H) 8.13 (d, J=2.45 Hz,1 H) 11.13 (br s, 1 H) 12.61 (br s, 1 H)6-chloro-N-(3,5-difluoro-6-methoxypyridin-2-yl)-7-fluoro-1H-indole-3-sulfonamideI-358

Basic LC-MS Method 2 (ES⁻): 390 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.58 (s, 3 H) 7.30 (t, J=7.34 Hz, 1 H) 7.61(d, J=8.31 Hz, 1 H) 7.90 (t, J=9.29 Hz, 1 H) 8.16 (s, 1 H) 10.84 (s, 1H) 12.82 (br s, 1 H)

N-[4-(cyanomethoxy)-2,5-difluorophenyl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide I-360

Neutral LCMS Method 3 (ES⁺): 415 (M+H)⁺, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 13.19 (s, 1H), 10.09 (s, 1H), 8.91 (d, J=3.0Hz, 1H), 8.42 (dd, J=8.5, 1.7 Hz, 1 H), 7.89-7.82 (m, 2H), 7.66 (d,J=8.7 Hz, 1 H), 7.57 (dd, J=8.2, 4.3 Hz, 1H), 7.22 (td, J=11.6, 7.3 Hz,2H), 5.16 (s, 2H).

N-[4-(cyanomethyl)-2,5-difluorophenyl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide I-361

Neutral LCMS Method 3 (ES⁺): 399 (M+H)⁺, 96% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 13.24 (s, 1H), 10.49 (s, 1H), 8.91 (dd,J=4.3, 1.7 Hz, 1H), 8.43 (dd, J=8.2, 1.7 Hz, 1H), 8.02-7.95 (m, 2H),7.69 (d, J=8.7 Hz, 1H), 7.57 (dd, J=8.2, 4.3 Hz, 1H), 7.30 (dd, J=10.8,6.5 Hz, 1H), 7.20 (dd, J=10.4, 6.7 Hz, 1H), 3.91 (s, 2H).

N-[4-(2-cyanoethyl)-2,5-difluorophenyl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide I-362

Neutral LCMS Method 3 (ES⁺): 413 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 13.22 (s, 1H), 10.33 (s, 1H), 8.91 (dd,J=4.3, 1.6 Hz, 1H), 8.43 (dd, J=8.2, 1.7 Hz, 1H), 7.95 (s, 1H), 7.92 (d,J=8.7 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.57 (dd, J=8.2, 4.3 Hz, 1H),7.17 (ddd, J=17.9, 10.7, 6.6 Hz, 2H), 2.79 (t, J =7.2 Hz, 2H), 2.76-2.71(m, 2H).

6-chloro-N-[3,6-difluoro-5-(2-fluoroethoxy)pyridin-2-yl]-1H-indole-3-sulfonamideI-364

Basic LC-MS Method 2 (ES⁺): 406 (M+H)⁺, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 4.24-4.29 (m, 1H) 4.31-4.36 (m, 1H)4.60-4.65 (m, 1H) 4.72-4.77 (m, 1H) 7.18 (dd, J=8.61, 1.72 Hz, 1H) 7.51(d, J=1.48 Hz, 1H) 7.70 (d, J=8.86 Hz, 1H) 7.78 (dd, J=9.84, 8.37 Hz,1H) 7.95 (d, J=2.95 Hz, 1H) 10.49 (s, 1H) 12.06 (brs, 1H).

6-chloro-N-[3,6-difluoro-5-(2-methoxyethoxy)pyridin-2-yl]-1H-indole-3-sulfonamideI-365

Basic LC-MS Method 2 (ES⁺): 418 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.24 (s, 3H) 3.58-3.60 (m, 2H) 4.12-4.17 (m,2H) 7.17 (dd, J=8.31, 1.96 Hz, 1H) 7.50 (d, J=1.96 Hz, 1H) 7.68 (d,J=8.80 Hz, 1H) 7.71-7.77 (m, 1H) 7.93 (d, J=2.45 Hz, 1H) 10.41 (brs, 1H)12.05 (brs, 1H).

6-chloro-7-(difluoromethoxy)-N-(3,5-difluoro-6-methoxypyridin-2-yl)-1H-indole-3-sulfonamideI-366

Basic LC-MS Method 2 (ES⁺): 440 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.55 (s, 3H) 7.21 (t, J=73.2 Hz, 1 H) 7.35(d, J=9.20 Hz, 1H) 7.73 (d, J=8.40 Hz, 1H) 7.90 (t, J=8.80 Hz, 1H) 8.09(s, 1H) 10.81 (s, 1H), 12.52 (brs, 1H).

6-chloro-N-(3,6-difluoro-5-methylpyridin-2-yl)-7-(trifluoromethyl)-1H-indole-3-sulfonamideI-367

Basic LC-MS Method 2 (ES⁺): 426 (M+H)⁺, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 2.09 (s, 3H) 7.53 (d, J=8.40 Hz, 1H)7.69-8.02 (m, 1H) 8.07 (s, 1H) 8.16 (d, J=8.40 Hz, 1H) 11.15 (brs, 1H)12.25 (brs, 1H).

D.5. Method F. Synthesis ofN-(2,1,3-benzoxadiazol-5-yl)-6-chloro-IH-indole-3-sulfonamide I-201

Step-1: Synthesis of1-(benzenesulfonyl)-N-(2,1,3-benzoxadiazol-5-yl)-6-chloro-indole-3-sulfonamideI-201a

In a sealed vial, 1-(benzenesulfonyI)-6-chloro-indole-3-sulfonylchloride XII-19 (192 mg, 0.49 mmol) was dissolved in pyridine (4 mL)under argon. 2,1,3-benzoxadiazol-5-amine (135 mg, 1 mmol) was added andstirred at room temperature overnight. The reaction mixture wasevaporated to dryness then the residue was taken into DCM. The organicphase was washed with HCI 1N and brine, dried over MgSO₄ and evaporated.The dark oil residue solidified on standing and was then triturated inACN/water (8/2), sonicated and filtered, washed with water and driedunder vacuum to provide 170 mg of1-(benzenesulfonyl)-N-(2,1,3-benzoxadiazol-5-yl)-6-chloro-indole-3-sulfonamideI-201a as a yellow solid.

Yield: 71%.

Basic LCMS Method 1 (ES⁻): 487 (M−H)⁻, 100% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 11.52 (s, 1H), 8.99 (s, 1H), 8.16-8.10 (m,2H), 7.98 (d, J =1.8 Hz, 1H), 7.91 (dd, J=9.1, 3.2 Hz, 2H), 7.63 (t,J=7.5 Hz, 1H), 7.56-7.51 (m, 2H), 7.43-7.36 (m, 2H), 7.25 (dd, J=9.6,1.9 Hz, 1H).

Step-2: Synthesis ofN-(2,1,3-benzoxadiazol-5-yl)-6-chloro-1H-indole-3-sulfonamide I-201

In a sealed tube,1-(benzenesulfonyl)-N-(2,1,3-benzoxadiazol-5-yl)-6-chloro-indole-3-sulfonamideI-201a (170 mg, 0.34 mmol) was suspended in methanol (4 mL). Water (1mL) was added, then potassium carbonate (200 mg, 1.45 mmol) and wasstirred at room temperature overnight. The reaction mixture wasevaporated to dryness. The residue was dissolved in EtOAc and washedwith HCI 1N and water, dried over MgSO₄ and evaporated. The residue waspurified over silica eluting with heptane/EtOAc (1/1). Afterevaporation, it provided 170 mg ofN-(2,1,3-benzoxadiazol-5-yl)-6-chloro-1H-indole-3-sulfonamide I-201 as abright yellow solid.

Yield: 88%.

Basic LCMS Method 1 (ES⁻): 347 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.27 (s, 1H), 11.22 (s, 1 H), 8.41 (d,J=2.8 Hz, 1H), 7.94 (d, J=9.5 Hz, 1H), 7.87 (d, J=8.6 Hz, 1 H), 7.54 (d,J=1.8 Hz, 1H), 7.38 (d, J=1.7 Hz, 1H), 7.34 (dd, J=9.5, 1.9 Hz, 1H),7.29 (dd, J=8.6, 1.9 Hz, 1H).

The following compounds in Table 7 may be synthesized according methodsanalogous to

Method F.

TABLE 7 Sul- Con- fonyl ditions, Con- Puri- chlor- Time ditions,fication ides Amines (Step- Yield Time con- Yield N° XII X 1) (%)(Step-2) ditions (%) I-202 XII- 246847- 80° C., crude K₂CO₃, Basic prep29 19 98-3 2 h MeOH, rt, LCMS overnight Method 1 I-203 XII- 367- rt, 194 K₂CO₃, DCM/ 28 19 34-0 h 30 MeOH, Heptane rt, 1 h I-204 XII- 2613-rt, 2 h 84 K₂CO₃, DCM/ 32 19 30-1 MeOH, MeOH rt, overnight I-205 XII-4519- 80° C., crude Cs₂CO₃, 10% 68 19 40-8 3 h MeOH, EtOAc/ rt, 2 hpetroleum ether I-206 XII- X-7 80° C., crude Cs₂CO₃, 20% 59 19 3 h MeOH,EtOAc/ rt, 2 h petroleum ether I-207 XII- X-8 80° C., crude Cs₂CO₃, 20%23 19 3 h MeOH, EtOAc/ rt, 2 h petroleum ether I-208 XII- 1268392- 80°C., crude Cs₂CO₃, 40% 32 19 91-1 3 h MeOH, EtOAc/ rt, 2 h petroleumether I-209 XII- 72115- 80° C., crude Cs₂CO₃, Recrystal- 55 19 06-1 2 hMeOH, lisation rt, 2 h in Et₂O I-210 XII- 1008112- 80° C., crude Cs₂CO₃,5% 13 19 39-7 2 h MeOH, MeOH/ rt, 2 h DCM I-211 XII- 74784- 80° C.,crude Cs₂CO₃, 25% 30 19 70-6 2 h MeOH, EtOAc/ rt, 2 h DCM I-212 XII-367- 100° C., crude Cs₂CO₃, 5% 35 19 24-8 2 h MeOH, MeOH/ rt, 2 h DCMI-213 XII- 112279- 100° C., crude Cs₂CO₃, 1% 58 19 60-4 2 h MeOH, MeOH/rt, 2 h DCM I-214 XII- 116759- 100° C., crude Cs₂CO₃, 1% 34 19 33-2 2 hMeOH, MeOH/ rt, 2 h DCM I-215 XII- 1240257- 100° C., crude Cs₂CO₃, 5% 6119 25-3 2 h MeOH, MeOH/ rt, 2 h DCM I-216 XII- 767- 100° C., crudeCs₂CO₃, 5% 17 19 63-5 2 h MeOH, MeOH/ rt, 2 h DCM I-217 XII- 2993- 100°C., crude Cs₂CO₃, 5% 68 19 24-0 2 h MeOH, MeOH/ rt, 2 h DCM I-218 XII-106- 100° C., crude Cs₂CO₃, 5% 51 19 40-1 2 h MeOH, MeOH/ rt, 2 h DCMI-219 XII- 73792- 100° C., crude Cs₂CO₃, 6% 40 19 22-0 2 h MeOH, MeOH/rt, 2 h DCM I-220 XII- 63069- 100° C., crude Cs₂CO₃, 5% 34 21 50-1 2 hMeOH, MeOH/ rt, 2 h DCM I-221 XII- 2613- 80° C., crude Cs₂CO₃, 5% 58 2230-1 1 h MeOH, MeOH/ rt, 2 h DCM I-222 XII- 63069- 100° C., crudeCs₂CO₃, 5% 27 23 50-1 1 h MeOH, MeOH/ rt, 2 h DCM I-223 XII- 367- rt, 1h 85 K₂CO₃, Basic prep 23 20 34-0 MeOH, LCMS rt, 1 h Method 1 I-224 XII-57946- rt, 16 h crude K₂CO₃, Basic prep 25 20 56-2 MeOH, LCMS rt, 16 hMethod 1 I-225 XII- 120934- rt, 16 h crude K₂CO₃, Basic prep 14 20 03-4MeOH, LCMS rt, 16 h Method 1 I-226 XII- X-1 rt, 16 h crude K₂CO₃, Basicprep 19 20 MeOH, LCMS rt, 16 h Method 1 I-227 XII- 2613- rt, 2 h 58K₂CO₃, Basic prep 49 20 30-1 MeOH, LCMS rt, 16 h Method 1 I-228 XII-112279- rt, 2 h 44 K₂CO₃, Basic prep 39 20 60-4 MeOH, LCMS rt, 3 hMethod 1 I-266 XII- 1341923- rt, 16 h 77 K₂CO₃, 0-5% 77 20 15-6 Dioxane,MeOH/ 105° C., DCM 24 h I-267 XII- 1341923- 50° C., crude K₂CO₃, Basicprep 51 19 15-6 48 h Dioxane, LCMS 100° C., Method 1 48 h I-268 XII-3710- rt, 16 h 89 K₂CO₃, 0-5% 60 20 42-7 Dioxane, MeOH/ 105° C., DCM 24h I-269 XII- 114973- 50° C., crude K₂CO₃, Basic 10 19 22-7 48 h Dioxane,prep 100° C., LCMS 48 h Method 1 I-270 XII- 3710- 50° C., crude K₂CO₃,Basic 59 19 42-7 48 h Dioxane, prep 100° C., LCMS 48 h Method 1 I-271XII- 2613- rt, 16 h 36 K₂CO₃, Recrystal- 27 33 30-1 Dioxane, lisation105° C., in ACN 6 days I-272 XII- 112279- rt, 1 h 40 K₂CO₃, 0-10% 25 3460-4 MeOH, MeOH/ 90° C., DCM 5 days I-273 XII- 123572- rt, 16 h 67K₂CO₃, Recrystal- 34 20 58-7 Dioxane, lisation 105° C., in ACN 48 hI-274 XII- 1008112- rt, 2 h 30 K₂CO₃, 0-5% 30 22 39-7 Dioxane, MeOH/105° C., DCM 24 h I-275 XII- 358672- 50° C., crude K₂CO₃, Basic prep 1319 65-8 16 h Dioxane, LCMS 100° C., Method 1 3 days I-276 XII- 123572-rt, 16 h 71 K₂CO₃, 50-0% 38 19 58-7 Dioxane, Heptane/ 105° C., DCM 48 hI-277 XII- 2613- rt, 16 h 38 K₂CO₃, Recrystal- 20 35 30-1 Dioxane,lisation 105° C., in ACN 3 days I-278 XII- 57946- rt, 16 h 44 K₂CO₃,0-40% 47 36 56-2 MeOH, EtOAc/ 50° C., Hexane 16 h I-279 XII- 1211590-50° C., crude K₂CO₃, Basic prep 20 19 31-6 16 h Dioxane, LCMS 100° C.,Method 1 3 days I-280 XII- 20511- 50° C., crude K₂CO₃, Basic prep 31 1912-0 16 h Dioxane, LCMS 100° C., Method 1 3 days I-281 XII- 2613- rt, 2h 86 K₂CO₃, Recrystal- 30 34 30-1 Dioxane, lisation 105° C., in ACN 28 hI-282 XII- 1341923- rt, 16 h 95 K₂CO₃, Recrystal- 25 35 15-6 Dioxane,lisation 105° C., in ACN 24 h I-283 XII- 1008112- rt, 2 h 40 K₂CO₃,0-10% 48 34 39-7 MeOH, MeOH/ 70° C., DCM 4 days I-284 XII- X-17 rt, 16 h85 K₂CO₃, DCM 3 20 Dioxane, 105° C., 24 h I-285 XII- 112279- 80° C.,crude K₂CO₃, 5% 28 22 60-4 2 h rt, 2 h EtOAc/ DCM I-286 XII- 1441723-80° C., crude Cs₂CO₃, 20% 65 19 24-5 4 h rt, 2 h EtOAc/ Petroleum etherI-287 XII- 69409- 80° C., crude K₂CO₃, 5% 15 22 98-9 2 h rt, 1.5 hEtOAc/ DCM Crystal- lization in EtOAc/ Petroleum ether I-288 XII-1441723- 80° C., crude Cs₂CO₃, 5% 12 22 24-5 2 h rt, 3 h EtOAc/ DCMI-290 XII- 246847- 80° C., crude Cs₂CO₃, 7.5% 45 6 98-3 2 h rt, 2 hEtOAc/ DCM I-291 XII- 112279- 80° C., crude K₂CO₃, DCM 17 22 61-5 1night rt, 2 h I-292 XII- 1441723- 80° C., crude Cs₂CO₃, 50% 24 20 24-5 2h rt, 2 h EtOAc/ 80° C., Petroleum ether I-293 XII- 367- 2 h crudeCs₂CO₃, 5% 22 22 24-8 80° C., rt, 3 h EtOAc/ DCM I-294 XII- 63069- 2 hcrude K₂CO₃, 5% 39 37 50-1 80° C., rt, 2 h EtOAc/ DCM I-295 XII-1240257- 2 h crude Cs₂CO₃, 5% 20 7 25-3 80° C., rt, 3 h EtOAc/ DCM I-296XII- 69409- 2 h crude Cs₂CO₃, 5% 29 7 98-9 80° C., rt, 1.5 h EtOAc/ DCMI-297 XII- 852062- 2 h crude Cs₂CO₃, 5% 4 19 17-0 80° C., rt, 4 h MeOH/DCM I-298 XII- 394223- 2 h crude Cs₂CO₃, 5% 60 19 61-1 80° C., rt, 3 hEtOAc/ DCM I-299 XII- 69409- 2 h crude Cs₂CO₃, 5% 38 19 98-9 80° C., rt,4 h MeOH/ DCM I-300 XII- 2613- 2 h crude K₂CO₃, 5% 60 37 30-1 80° C.,rt, 3 h EtOAc/ DCM I-301 XII- 81282- 80° C., crude Cs₂CO₃, 20% 39 1960-2 3 h rt, 2 h EtOAc/ DCM I-302 XII- 732306- 80° C., crude Cs₂CO₃, 30%35 19 31-9 16 h rt, 2 h EtOAc/ Petroleum ether I-303 XII- 114973- 0° C.,17 K₂CO₃, 30-50% 48 20 22-7 5 h Dioxane/ EtOAc/ water, 4 h heptane I-307XII- X-14 70° C., — Depro- Basic 6 20 20 h tection prep during LCMSstep-1 Method 1 I-308 XII- 155906- 80° C., crude K₂CO₃, 5% to 14 19 13-115 h 70 ° C., 20% Dioxane/ DCM/ water 24 h Petroleum ether I-336 XII-X-21 120° C., — Depro- 5% 23 20 2 h tection EtOH/ during DCM step-1I-363 XII- 1341923- rt, 16 h 30 TBAF, 5% 50 45 15-6 THF, MeOH/ 35° C.,DCM 6 days

6-chloro-N-(5-chloro-3-fluoropyridin-2-yl)-1H-indole-3-sulfonamide I-202

Basic LCMS Method 1 (ES⁻F): 360 (M+H)⁺, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.25 (s, 1H), 11.07 (s, 1 H), 8.08 (d,J=3.5 Hz, 2H), 7.95 (d, J=10.1 Hz, 1H), 7.87 (d, J=8.6 Hz, 1H), 7.55 (s,1H), 7.23 (m, 1H) 6-chloro-N-(2,4,5-trifluorophenyl)-1H-indole-3-sulfonamide I-203

Basic LCMS Method 1 (ES⁻F): 361.2 (M-FH)+, 100% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 11.29 (s, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.57(d, J=1.9 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.14-7.00 (m, 2H), 6.94 (td,J=11.1, 8.1 Hz, 1H).

6-chloro-N-(4-chloro-2,5-difluorophenyl)-1 H-indole-3-sulfonamide I-204

Basic LCMS Method 1 (ES⁻): 375.2 (M−H)⁻, 100% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 1H), 10.46 (s, 1H), 8.04 (d, J=2.8Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.59-7.47 (m, 2H), 7.34 (dd, J=10.4,7.0 Hz, 1H), 7.23 (dd, J =8.6, 1.9 Hz, 1H).

6-chloro-N-(2,3-difluorophenyI)-1H-indole-3-sulfonamide I-205

Neutral LCMS Method 3 (ES⁺): 343.2 (M+H)⁺, 97% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.08 (s, 1H), 10.24 (s, 1H), 7.94 (s, 1H),7.72 (d, J=8.6 Hz, 1H), 7.53 (s, 1H), 7.21 (d, J=8.6 Hz, 1H), 7.01-7.17(m, 3H).

6-chloro-N-[4-(cyanomethyl)-2-fluorophenyl]-1H-indole-3-sulfonamideI-206

Neutral LCMS Method 3 (ES⁺): 364.1 (M+H)⁺, 98% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.04 (s, 1H), 10.04 (s, 1H), 7.90 (s, 1H),7.73 (d, J=8.6 Hz, 1H), 7.52 (s, 1H), 7.32 (s, 1H), 7.19 (d, J=8.6 Hz,1H), 7.07 (d, J=7.0 Hz, 2H), 3.95 (s, 2H).

6-chloro-N-[4-(1-cyanoethyl)-2-fluorophenyl]-1H-indole-3-sulfonamideI-207

Neutral LCMS Method 3 (ES⁺): 378.2 (M+H)⁺, 94% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 10.12 (s, 1 H), 8.01 (s, 1 H), 7.70-7.71 (m,2H), 7.34 -7.36 (m, 1 H), 7.09-7.25 (m, 3H), 4.23 (q, J=7.2 Hz, 1 H),1.48 (d, J=7.2 Hz, 3H).

6-chloro-N-(4-chloro-5-fluoro-2-methoxyphenyl)-1 H-indole-3-sulfonamideI-208

Neutral LCMS Method 3 (ES⁺): 389.2 (M+H)⁺, 95% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.03 (s, 1H), 9.63 (s, 1H), 7.95 (s, 1H),7.80 (d, J=8.6 Hz, 1H), 7.50 (d, J=1.9 Hz, 1H), 7.34-7.16 (m, 2H), 7.03(d, J=6.9 Hz, 1H), 3.39 (s, 3H).

6-chloro-N-(4-cyano-3-methylphenyI)-1H-indole-3-sulfonamide I-209

Neutral LCMS Method 3 (ES⁺): 346 (M+H)⁺, 95% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.16 (s, 1H), 10.87 (s, 1H), 8.20 (s, 1H),7.82 (d, J=8.5 Hz, 1H), 7.68-7.41 (m, 2H), 7.24 (dd, J=8.6, 2.0 Hz, 1H),7.10 (d, J=2.1 Hz, 1H), 7.06 (dd, J=8.5, 2.2 Hz, 1 H), 2.33 (s, 3H).

6-chloro-N-(4-ethynyl-2-fluorophenyl)-1 H-indole-3-sulfonamide I-210

Neutral LCMS Method 3 (ES⁺): 349 (M+H)⁺, 96% purity.

¹H NMR (600 MHz, DMSO-d₆) δ: 12.08 (s, 1H), 10.25 (s, 1H), 7.95 (s, 1H),7.77 (d, J=8.5 Hz, 1H), 7.51 (s, 1H), 7.35-7.32 (m, 1H), 7.23-7.18 (m,3H), 4.17 (s, 1H).

6-chloro-N[5-(trifluoromethyppyridin-2-yl]-1H-indole-3-sulfonamide I-211

Neutral LCMS Method 3 (ES⁺): 376.4 (M+H)⁺, 84% purity.

¹H NMR (600 MHz, DMSO-d₆) δ: 12.17 (s, 1H), 11.62 (s, 1H), 8.49 (d,J=2.6 Hz, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.98 (dd, J=8.8, 2.5 Hz, 1H),7.88 (d, J=8.6 Hz, 1H), 7.51 (d, J =1.9 Hz, 1H), 7.24 (dd, J=8.7, 2.0Hz, 1H), 7.22 (d, J=8.9 Hz, 1H).

N-(4-bromo-2-fluorophenyl)-6-chloro-1 H-indole-3-sulfonamide I-212

Neutral LCMS Method 3 (ES⁺): 405 (M+H)⁺, 95% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 12.05 (s, 1H), 10.08 (s, 1H), 7.89 (d,J=1.5 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.51 (d, J=1.9 Hz, 1H), 7.41 (dd,J=10.0, 2.2 Hz, 1H), 7.31-7.26 (m, 1H), 7.23 (t, J=8.5 Hz, 1H), 7.19(dd, J=8.6, 1.9 Hz, 1H).

N-(4-bromo-2,5-difluorophenyI)-6-chloro-1H-indole-3-sulfonamide I-213

Neutral LCMS Method 3 (ES⁺): 402.9 (M+H)⁺, 97% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 12.12 (s, 1H), 10.45 (s, 1H), 8.04 (d,J=2.9 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.59 (dd, J=9.6, 6.4 Hz, 1H),7.52 (d, J =1.9 Hz, 1H), 7.30 (dd, J=9.9, 6.8 Hz, 1H), 7.22 (dd, J=8.6,1.9 Hz, 1H).

6-chloro-N-(4-chloro-2-fluoro-5-methylphenyI)-1H-indole-3-sulfonamideI-214

Neutral LCMS Method 3 (ES⁺): 472.9 (M+H)⁺, 98% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 12.03 (s, 1H), 10.00 (s, 1H), 7.91 (s, 1H),7.73 (d, J=8.6 Hz, 1H), 7.51 (d, J=1.9 Hz, 1H), 7.26 (t, J=9.4 Hz, 2H),7.19 (dd, J=8.6, 1.9 Hz, 1H), 3.29 (s, 3H).

6-chloro-N-[2-fluoro-4-(pentafluoro-lambda-6-sulfanyl)phenyl]-1H-indole-3-sulfonamideI-215

Neutral LCMS Method 3 (ES⁻): 448.9 (M−H)⁻, 96% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 12.16 (s, 1H), 10.72 (s, 1H), 8.08 (d,J=3.0 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.80 (dd, J=2.5, 15 Hz, 1H), 7.64(dd, J=9.1, 2.5 Hz, 1H), 7.62-7.57 (m, 1 H), 7.52 (d, J=1.7 Hz, 1H),7.22 (dd, J=8.6, 1.9 Hz, 1 H).

N-(2,1,3-benzoxadiazol-4-yl)-6-chloro-1H-indole-3-sulfonamide I-216

Neutral LCMS Method 3 (ES⁻F): 348.9 (M+H)⁺, 95% purity.

¹H NMR (600 MHz, DMSO-d₆) δ: 12.17 (d, J=3.2 Hz, 1H), 11.28 (s, 1H),8.17 (d, J=3.0 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H),7.49 (d, J=1.9 Hz, 1H), 7.45 (dd, J=9.0, 7.2 Hz, 1 H), 7.24 (d, J=7.2Hz, 1H), 7.20 (dd, J=8.6, 1.9 Hz, 1 H).

6-chloro-N[4-(pentafluoro-lambda6-sulfanyl)phenyl]-1H-indole-3-sulfonamideI-217

Neutral LCMS Method 3 (ES⁻): 431 (M−H)⁻, 98% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 12.15 (s, 1H), 10.90 (s, 1H), 8.14 (s, 1H),7.82 (d, J=8.6 Hz, 1H), 7.77-7.62 (m, 2H), 7.51 (d, J=1.9 Hz, 1H),7.29-7.16 (m, 3H).

N-(4-bromophenyl)-6-chloro-1 H-indole-3-sulfonamide I-218

Neutral LCMS Method 3 (ES⁻): 484.9 (M−H)⁻, 95% purity.

¹H NMR (600 MHz, DMSO-d₆) δ: 12.06 (s, 1H), 10.35 (s, 1H), 8.00 (s, 1H),7.79 (d, J=8.6 Hz, 1H), 7.49 (d, J=1.9 Hz, 1H), 7.37-7.30 (m, 2H), 7.21(dd, J=8.6, 2.0 Hz, 1H), 7.06-6.98 (m, 2H).

N-(4-acetyl-2-fluorophenyl)-6-chloro-1H-indole-3-sulfonamide I-219

Neutral LCMS Method 3 (ES⁻): 365 (M−H)⁻, 99% purity.

¹H NMR (500 MHz, DMSO-d₆): δ 12.12 (s, 1H), 10.58 (s, 1H), 8.06 (d,J=2.2 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.66 (dd, J=8.5, 2.0 Hz, 1H),7.60 (dd, J=11.4, 1.9 Hz, 1H), 7.55-7.48 (m, 2H), 7.22 (dd, J=8.6, 1.9Hz, 1H), 2.46 (s, 3H).

N-(4-cyano-2-fluorophenyl)-6-(cyclopropylmethoxy)-1H-indole-3-sulfonamideI-220

Neutral LCMS Method 3 (ES⁻F): 403 (M-FNH₄)+, 96% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 11.81 (d, J=3.0 Hz, 1H), 10.68 (s, 1H),7.91 (d, J=2.9 Hz, 1H), 7.71 (dd, J=10.7, 1.7 Hz, 1H), 7.67 (d, J=8.8Hz, 1H), 7.61-7.46 (m, 2H), 6.90 (d, J=2.2 Hz, 1H), 6.83 (dd, J=8.8, 2.2Hz, 1H), 3.80 (d, J=6.9 Hz, 2H), 1.32-1.14 (m, 1H), 0.68-0.51 (m, 2H),0.37-0.15 (m, 2H).

N-(4-chloro-2,5-difluorophenyI)-6-methoxy-1H-indole-3-sulfonamide I-221

Neutral LCMS Method 3 (ES⁻F): 373 (M-FH)+, 97% purity.

¹H NMR (500 MHz, DMSO-d₆) δ:11.79 (s, 1H), 10.35 (s, 1H), 7.86 (d, J=2.9Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.50 (dd, J=9.9, 6.9 Hz, 1H), 7.32 (dd,J=10.5, 6.9 Hz, 1H), 6.93 (d, J=2.2 Hz, 1H), 6.82 (dd, J=8.8, 2.3 Hz,1H), 3.76 (s, 3H).

N-(4-cyano-2-fluorophenyl)-6-(tetrahydrofuran-2-ylmethoxy)-1H-indole-3-sulfonamideI-222

Neutral LCMS Method 3 (ES⁺): 316 (M+H)⁺, 97% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 11.83 (s, 1H), 10.68 (s, 1H), 7.92 (d,J=3.0 Hz, 1H), 7.71 (dd, J=10.7, 1.7 Hz, 1 H), 7.68 (d, J=8.8 Hz, 1H),7.60-7.46 (m, 2H), 6.94 (d, J=2.3 Hz, 1H), 6.83 (dd, J=8.8, 2.3 Hz, 1H),4.14 (qd, J=6.7, 4.2 Hz, 1H), 3.92 (qd, J=10.1, 5.1 Hz, 2H), 3.78 (dt,J=8.2, 6.7 Hz, 1H), 3.66 (td, J=7.7, 6.2 Hz, 1H), 1.99 (dddd, J=12.2,8.5, 7.2, 5.3 Hz, 1H), 1.92-1.74 (m, 2H), 1.67 (ddt, J=12.0, 8.6, 6.9Hz, 1H).

6-chloro-N-(2,4,5-trifluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide I-223

Basic LCMS Method 1 (ES⁺): 362.2 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.83 (s, 1H), 10.27 (s, 1H), 8.19-7.98 (m,2H), 7.47 (m, J=10.0 Hz, 1H), 7.37 (m, J=9.2 Hz, 2H).

6-chloro-N-(4-chloro-2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide I-224

Basic LCMS Method 1 (BSI: 360.2 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.80 (s, 1H), 10.17 (s, 1H), 8.12 (d, J=8.3Hz, 1H), 8.04 (s, 1H), 7.34 (m, J=8.8 Hz, 2H), 7.28 (t, J=8.6 Hz, 1H),7.18 (d, J=8.6 Hz, 1H).

6-chloro-N-(2,2,6-trifluoro-1,3-benzodioxo1-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamideI-225

Basic LCMS Method 1 (BSI: 406.2 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.78 (s, 1H), 10.15 (s, 1H), 8.10 (d, J=8.4Hz, 1H), 8.04 (s, 1H), 7.43 (d, J=9.1 Hz, 1H), 7.34 (m, J=7.3, 4.5 Hz,2H).

6-chloro-N-(7-fluoro-2,1,3-benzothiadiazo1-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamideI-226

Basic LCMS Method 1 (BSI: 384.2 (M+H)⁺, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.78 (s, 1H), 10.79 (s, 1H), 8.22-8.12 (m,2H), 7.51-7.39 (m, 2H), 7.29 (d, J=8.3 Hz, 1H).

6-chloro-N-(4-chloro-2,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide I-227

Basic LCMS Method 1 (ES⁻): 376.2 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.87 (s, 1H), 10.52 (s, 1H), 8.26-8.12 (m,2H), 7.55 (dd, J=9.9, 6.8 Hz, 1H), 7.37 (dd, J=9.5, 7.0 Hz, 2H).

N-(4-bromo-2,5-difluorophenyl)-6-chloro-1H-pyrrolo[2,3-1D]pyridine-3-sulfonamideI-228

Basic LCMS Method 1 (ES⁻): 420 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.87 (s, 1H), 10.52 (s, 1H), 8.25-8.15 (m,2H), 7.63 (dd, J=9.7, 6.4 Hz, 1 H), 7.38 (d, J=8.3 Hz, 1H), 7.34 (dd,J=9.7, 6.8 Hz, 1 H).

6-chloro-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-1H-pyrrolo[2,3-1]pyridine-3-sulfonamideI-266

Basic LCMS Method 1 (ES⁺): 410 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.85 (s, 1H), 10.38 (s, 1H), 8.15 (d, 1H),8.13 (d, J=8.4 Hz, 1 H), 7.38-7.34 (d, 1 H), 7.34-7.27 (m, 2H), 7.08 (t,J=72.9 Hz, 1 H).

6-chloro-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-1H-indole-3-sulfonamide I-267

Basic LCMS Method 1 (ES⁻): 407 (M−H)⁻, 97% purity.

6-chloro-N-(2,5-difluoro-4-methylphenyl)-1H-pyrrolo[2,3-1]pyridine-3-sulfonamideI-268

Basic LCMS Method 1 (ES⁻F): 358 (M+H)⁺, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.80 (s, 1H), 10.19 (s, 1H), 8.18-8.07 (m,2H), 7.36 (d,

J=8.3 Hz, 1H), 7.06 (ddd, J=11.0, 6.7, 2.2 Hz, 2H), 2.12 (s, J=1.9 Hz,3H).

6-chloro-N-[2,5-difluoro-4-(trifluoromethyl)phenyI]-1H-indole-3-sulfonamideI-269

Basic LCMS Method 1 (ES⁻): 409 (M−H)⁻, 100% purity.

6-chloro-N-(2,5-difluoro-4-methylphenyI)-1H-indole-3-sulfonamide I-270

Basic LCMS Method 1 (ES⁻F): 357 (M+H)⁺, 99% purity

N-(4-chloro-2,5-difluorophenyl)-5H-[1,3]dioxolo[4,5-f]indole-7-sulfonamideI-271

Basic LCMS Method 1 (ES⁻): 385 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 11.81 (s, 1H), 10.37 (s, 1H), 7.81 (d, J=3.1Hz, 1H), 7.54 (dd, J=10.0, 6.9 Hz, 1H), 7.33 (dd, J=10.6, 7.0 Hz, 1H),7.25 (s, 1H), 6.97 (s, 1H), 6.00 (s, 2H).

N-(4-bromo-2,5-difluorophenyl)-6-methoxy-1H-pyrrolo[2,3-b]pyridine-3-sulfonamideI-272

Basic LCMS Method 1 (ES⁺): 418 (M+H)⁺, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.45 (s, 1H), 10.43 (s, 1H), 8.04 (d, J=8.6Hz, 1H), 7.88 (d, J=3.0 Hz, 1H), 7.62 (dd, J=9.7, 6.4 Hz, 1H), 7.32 (dd,J=9.9, 6.9 Hz, 1H), 6.73 (d, J=8.6 Hz, 1H), 3.87 (s, 3H).

6-chloro-N-[2-fluoro-4-(trifluoromethoxy)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide I-273

Basic LCMS Method 1 (ES⁺): 410 (M+H)⁺, 99% purity. ¹H NMR (400 MHz,DMSO-d₆) δ 12.83 (s, 1H), 10.23 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 8.06(d, J=8.4 Hz, 1H), 7.39 (t, J=8.9 Hz, 1H), 7.32 (dd, J=8.1, 2.6 Hz, 2H),7.21-7.13 (m, 1H).

N-(4-ethynyl-2-fluorophenyl)-6-methoxy-1 H-indole-3-sulfonamide I-274

Basic LCMS Method 1 (ES⁻): 343 (M−H)⁻, 96% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 11.76 (s, J=3.0 Hz, 1H), 10.17 (s, 1H), 7.78(d, J=2.8 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.34 (t, J=8.3 Hz, 1H),7.26-7.13 (m, 2H), 6.93 (d, J=2.2 Hz, 1H), 6.81 (dd, J=8.8, 2.2 Hz, 1H),4.18 (s, 1H), 3.77 (s, 3H).

N-(5-bromo-6-chloropyridin-2-yl)-6-chloro-1H-indole-3-sulfonamide I-275

Basic LCMS Method 1 (ES⁻): 418 (M−H)⁻, 96% purity6-chloro-N-[2-fluoro-4-(trifluoromethoxy)phenyl]-1H-indole-3-sulfonamide I-276

Basic LCMS Method 1 (ES⁻): 407 (M−H)⁻, 96% purity. ¹H NMR (400 MHz,DMSO-d₆) δ 12.08 (s, 1H), 10.15 (s, 1H), 7.92 (d, J=2.7 Hz, 1H), 7.67(d, J=8.6 Hz, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.39 (t, J=8.9 Hz, 1H), 7.29(dd, J=10.6, 2.7 Hz, 1H), 7.16 (ddd, J=11.4, 8.9, 2.2 Hz, 2H).

N-(4-chloro-2,5-difluorophenyl)-6-cyano-1H-indole-3-sulfonamide I-277

Basic LCMS Method 1 (ES⁻): 366 (M−H)⁻, 100% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.56 (s, 1H), 10.54 (s, 1H), 8.26 (d, J=2.4Hz, 1H), 8.00 (d, J=1.3 Hz, 1H), 7.94 (d, J=8.4 Hz, 1 H), 7.63-7.47 (m,2H), 7.36 (dd, J=10.3, 6.9 Hz, 1H).

6-bromo-N-(4-chloro-2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide I-278

Basic LCMS Method 1 (ES⁻): 402 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.85 (s, 1H), 10.20 (s, 1H), 8.04 (d, J=8.3Hz, 2H), 7.48 (d, J=8.3 Hz, 1H), 7.35 (dd, J=10.3, 2.3 Hz, 1H), 7.29 (t,J=8.5 Hz, 1H), 7.19 (ddd, J=8.6, 2.3, 1.0 Hz, 1H).

6-chloro-N-(3-fluoro-5-methylpyridin-2-yl)-1H-indole-3-sulfonamide I-279

Basic LCMS Method 1 (ES⁻): 338 (M−H)⁻, 99% purity.6-chloro-N-(5-iodopyridin-2-yl)-1H-indole-3-sulfonamide I-280

Basic LCMS Method 1 (ES⁻): 432 (M−H)⁻, 91% purity.N-(4-chloro-2,5-difluorophenyl)-6-methoxy-1H-pyrrolo[2,3-b]pyridine-3-sulfonamideI-281

Basic LCMS Method 1 (ES⁺): 374 (M+H)⁺, 100% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.45 (s, J=2.9 Hz, 1H), 10.42 (s, 1H), 8.04(d, J=8.6 Hz, 1H), 7.88 (d, J=2.9 Hz, 1H), 7.54 (dd, J=9.9, 6.8 Hz, 1H),7.36 (dd, J=10.4, 6.9 Hz, 1H), 6.73 (d, J=8.6 Hz, 1H), 3.88 (s, 3H).

6-cyano-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-1H-indole-3-sulfonamide I-282

Basic LCMS Method 1 (ES⁻): 398 (M−H)⁻, 100% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.54 (s, 1H), 10.40 (s, 1H), 8.22 (d, J=2.8Hz, 1H), 8.00 (dd, J=1.4, 0.7 Hz, 1 H), 7.88 (d, J=8.3 Hz, 1 H), 7.55(dd, J=8.4, 1.4 Hz, 1 H), 7.38-7.25 (m, 2H), 7.16 (s, 1H).

N-(4-ethynyl-2-fluorophenyl)-6-methoxy-1H-pyrrolo[2,3-b]pyridine-3-sulfonamideI-283

Basic LCMS Method 1 (ES⁺): 346 (M+H)⁺, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.4 (s, 1H), 10.21 (s, 1H), 8.00 (d, J=8.7Hz, 1H), 7.76 (s, 1 H), 7.35 (d, J=8.0 Hz, 1 H), 7.20 (m, 2H), 6.70 (d,J=8.6 Hz, 1 H) 4.20 (s, 1H), 3.87 (s, 3H).

6-chloro-N-(6-fluoro-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamideI-284

Basic LCMS Method 1 (ES⁻): 380 (M−H)⁻, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.83 (s, 1H), 10.48 (s, 1H), 8.15 (d, J=8.3Hz, 1H), 8.11 (d, J=2.4 Hz, 1H), 7.68 (d, J=6.9 Hz, 1H), 7.47 (d, J=9.5Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 5.30 (s, 2H).

N-(4-bromo-2,5-difluorophenyl)-6-methoxy-1 H-indole-3-sulfonamide I-285

Neutral LCMS Method 3 (ES⁺): 417 (M+H)⁺, 98% purity 1H NMR (500 MHz,DMSO-d₆) δ: 11.79 (d, J=3.0 Hz, 1H), 10.37 (s, 1H), 7.87 (d, J=2.9 Hz,1H), 7.65 (d, J=8.8 Hz, 1H), 7.58 (dd, J=9.7, 6.4 Hz, 1H), 7.29 (dd,J=10.0, 6.8 Hz, 1H), 6.93 (d, J=2.2 Hz, 1H), 6.82 (dd, J=8.8, 2.3 Hz,1H), 3.76 (s, 3H).

6-chloro-N-(4-cyano-5-fluoro-2-methoxyphenyI)-1H-indole-3-sulfonamideI-286

Neutral LCMS Method 3 (ES⁺): 380.7 (M+H)⁺, 97% purity.

¹H NMR (600 MHz, DMSO-d₆) δ: 12.19 (s, 1H), 10.27 (s, 1H), 8.23 (s, 1H),7.90 (d, J=8.6 Hz, 1H), 7.52 (s, 1H), 7.38-7.33 (m, 2H), 7.23 (dd,J=8.6, 1.9 Hz, 1H), 3.65 (s, 3H).

N-(2-fluoro-4-(trifluoromethyl)phenyI)-6-methoxy-1H-indole-3-sulfonamideI-287

Neutral LCMS Method 3 (ES⁺): 389 (M+H)⁺, 99% purity.

1H NMR (500 MHz, DMSO-d₆) δ: 11.79 (s, 1H), 10.48 (s, 1H), 7.86 (d,J=2.9 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.62-7.50 (m, 2H), 7.47-7.37 (m,1H), 6.92 (d, J=2.2 Hz, 1H), 6.81 (dd, J=8.8, 2.3 Hz, 1H), 3.75 (s, 3H).

N-(4-cyano-5-fluoro-2-methoxyphenyI)-6-methoxy-1H-indole-3-sulfonamideI-288

Neutral LCMS Method 3 (ES⁺): 376 (M+H)⁺, 98% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 11.86 (d, J=3.0 Hz, 1H), 10.11 (s, 1H),8.05 (d, J=2.9 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.35 (d, J=6.0 Hz, 1H),7.32 (d, J=11.2 Hz, 1H), 6.93 (d, J=2.3 Hz, 1H), 6.83 (dd, J=8.8, 2.3Hz, 1 H), 3.75 (s, 3H), 3.68 (s, 3H).

6-Bromo-N-(5-chloro-3-fluoropyridin-2-yl)-1 H-indole-3-sulfonamide I-290

Neutral LCMS Method 3 (ES⁺): 404 (M+H)⁺, 98% purity.

N-(4-cyano-2,5-difluorophenyl)-6-methoxy-1 H-indole-3-sulfonamide I-291

Neutral LCMS Method 3 (ES⁺): 381 (M+NH4)+, 98% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 11.93 (br s, 1 H), 11.11 (s, 1 H), 8.12 (d,J=3.0 Hz, 1H), 7.83 (dd, J=10.3, 6.0 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H),7.43 (dd, J=11.1, 6.4 Hz, 1H), 6.95 (d, J=2.3 Hz, 1H), 6.86 (dd, J=8.8,2.3 Hz, 1H), 3.77 (s, 3H).

6-chloro-N-(4-cyano-5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamideI-292

Neutral LCMS Method 3 (ES⁺): 381 (M+H)⁺, 95.0% purity.

¹H NMR (600 MHz, DMSO-d₆) δ: 12.90 (s, 1H), 10.36 (s, 1H), 8.40 (d,J=2.3 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 7.45-7.34 (m, 3H), 3.63 (s, 3H).

N-(4-bromo-2-fluorophenyl)-6-methoxy-1 H-indole-3-sulfonamide I-293

Neutral LCMS Method 3 (ES⁺): 399 (M+H)⁺, 98% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 11.72 (s, 1H), 9.97 (s, 1H), 7.71 (d, J=2.1Hz, 1 H), 7.61 (d, J=8.8 Hz, 1H), 7.40 (dd, J=10.0, 2.1 Hz, 1H),7.32-7.16 (m, 2H), 6.92 (d, J=2.3 Hz, 1H), 6.79 (dd, J=8.8, 2.3 Hz, 1H),3.76 (s, 3H).

N-(4-cyano-2-fluorophenyl)-6-(2,2,2-trifluoroethoxy)-1H-indole-3-sulfonamide I-294

Neutral LCMS Method 3 (ES⁺): 414 (M+H)⁺, 99% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 11.99 (d, J=2.9 Hz, 1H), 10.71 (s, 1H),7.98 (d, J=2.9 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.71 (dd, J=10.7, 1.7Hz, 1H), 7.61-7.49 (m, 2H), 7.07 (d, J=2.3 Hz, 1H), 6.95 (dd, J=8.8, 2.3Hz, 1H), 4.75 (q, J=8.9 Hz, 2H).

6-chloro-N-[2-fluoro-4-(pentafluoro-lambda˜6˜sulfanyl)phenyl]-1H-pyrrolo[2,3-1]pyridine-3-sulfonamideI-295

Neutral LCMS Method 3 (ES⁺): 452 (M+H)⁺, 99% purity.

¹H NMR (600 MHz, DMSO-d₆) δ: 12.90 (s, 1H), 10.80 (s, 1H), 8.23 (s, 1H),8.22 (d, J=8.4 Hz, 1H), 7.82 (dd, J=10.9, 2.6 Hz, 1H), 7.64 (dd, J=9.2,2.5 Hz, 1H), 7.61-7.56 (m, 1H), 7.36 (d, J=8.3 Hz, 1H).

6-chloro-N-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide I-296

Neutral LCMS Method 3 (ES⁺): 394 (M+H)⁺, 95% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 12.87 (s, 1H), 10.64 (s, 1H), 8.20 (d,J=8.4 Hz, 1H), 8.18 (s, 1H), 7.64-7.52 (m, 2H), 7.50-7.42 (m, 1H), 7.35(d, J=8.3 Hz, 1H).6-chloro-N-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-1H-indole-3-sulfonamide I-297

Neutral LCMS Method 3 (ES⁺): 394 (M+H)⁺, 89% purity6-chloro-N-(2,5-difluoro-4-methoxyphenyI)-1H-indole-3-sulfonamide I-298

Neutral LCMS Method 3 (ES⁺): 373 (M-FH)+, 99% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 12.00 (s, 1H), 9.80 (s, 1H), 7.83 (s, 1H),7.69 (d, J=8.5 Hz, 1H), 7.51 (d, J=1.9 Hz, 1H), 7.19 (dd, J=8.6, 1.9 Hz,1H), 7.00 (ddd, J=11.6, 10.3, 7.7 Hz, 2H), 3.74 (s, 3H).

6-chloro-N-[2-fluoro-4-(trifluoromethyl)phenyl]-1 H-indole-3-sulfonamideI-299

Neutral LCMS Method 3 (ES⁺): 393 (M-FH)+, 98% purity.

¹H NMR (500 MHz, DMSO-d₆) 5 12.13 (d, J=2.9 Hz, 1H), 10.57 (s, 1H), 8.04(d, J=2.9 Hz, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.64-7.54 (m, 2H), 7.52 (d,J=1.9 Hz, 1H), 7.46 (dd, J =8.5, 2.1 Hz, 1H), 7.21 (dd, J=8.6, 1.9 Hz,1H).

N-(4-chloro-2,5-difluorophenyI)-6-(2,2,2-trifluoroethoxy)-1H-indole-3-sulfonamideI-300

Neutral LCMS Method 3 (ES⁺): 441 (M+H)⁺, 97% purity.

¹H NMR (600 MHz, DMSO-d₆) δ: 11.95 (d, J=3.1 Hz, 1H), 10.40 (s, 1H),7.92 (d, J=2.8 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.50 (dd, J=9.9, 6.8 Hz,1H), 7.32 (dd, J=10.5, 6.9 Hz, 1 H), 7.07 (d, J=2.3 Hz, 1H), 6.94 (dd,J=8.8, 2.3 Hz, 1 H), 4.76 (q, J=8.9 Hz, 2H).

6-chloro-N-(2-oxo-2,3-dihydro-1,3-benzoxazol-7-yl)-1H-indole-3-sulfonamideI-301

Neutral LCMS Method 3 (ES⁺): 364 (M+H)⁺, 94.0% purity.

¹H NMR (500 MHz, DMSO-d₆) δ: 12.04 (s, 1H), 11.55 (s, 1H), 10.18 (s,1H), 7.93 (s, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.52-7.48 (m, 1H), 7.16 (dd,J=8.6, 1.9 Hz, 1H), 6.98 (dd, J=8.3, 7.8 Hz, 1H), 6.87 (dd, J=8.4, 1.1Hz, 1H), 6.79 (dd, J=7.7, 1.1 Hz, 1H).

6-chloro-N-(3,5-difluoropyridin-2-yl)-1 H-indole-3-sulfonamide I-302

Neutral LCMS Method 3 (ES⁺): 344 (M+H)⁺, 97.8% purity ¹H NMR (600 MHz,DMSO-d₆) δ: 12.08 (s, 1H), 10.78 (s, 1H), 8.10 (s, 1H), 8.04 (s, 1H),7.89-7.80 (m, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.52 (s, 1H), 7.21 (dd,J=8.6, 1.9 Hz, 1H).

6-chloro-N-[2,5-difluoro-4-(trifluoromethyl)phenyI]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamideI-303

Basic LCMS Method 1 (ES⁻): 410 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.94 (s, 1 H), 11.04 (s, 1 H), 8.40 (d,J=2.9 Hz, 1 H), 8.28 (d, J=8.3 Hz, 1H), 7.71-7.60 (m, 1H), 7.48 (dd,J=12.1, 6.3 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H).

6-chloro-N-(5-chloro-3,6-difluoropyridin-2-yl)-1H-pyrrolo[2,3-1]pyridine-3-sulfonamideI-307

Basic LCMS Method 1 (ES⁺): 379 (M+H)⁺, 100% purity.

6-chloro-N-(2,5-difluoro-4-iodophenyl)-1 H-indole-3-sulfonamide I-308

Neutral LCMS Method 3 (ES⁺): 469 (M+H)⁺, 95% purity.

¹H NMR (600 MHz, DMSO-d₆) δ: 12.13 (d, J=3.0 Hz, 1H), 10.45 (s, 1H),8.04 (d, J=2.9 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.63 (dd, J=9.4, 5.7 Hz,1H), 7.52 (d, J=1.8 Hz, 1H), 7.23 (dd, J=8.6, 1.9 Hz, 1H), 7.20 (dd,J=9.1, 6.5 Hz, 1H).

6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-1H-pyrrolo[2,3-1]pyridine-3-sulfonamideI-336

Basic LCMS Method 1 (ES⁻): 389 (M−H)⁻, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.87 (s, 1H), 11.17 (s, 1H), 8.29 (dd,J=18.4, 5.6 Hz, 2H), 7.98 (d, J=9.0 Hz, 1H), 7.39 (d, J=8.4 Hz, 1 H),3.63 (s, 3H).

N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamideI-363

Basic LCMS Method 1 (ES⁻): 424 (M−H)⁻, 95% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.97 (s, 1H), 10.44 (s, 1H), 8.43-8.18 (m,2H), 7.59 (d, J=8.2 Hz, 1 H), 7.43-6.85 (m, 4H)

D.6. Method G: Synthesis ofN-(4-cyano-2-fluorophenyl)-6-(pyridin-3-yl)-1H-indole-3-sulfonamideI-229

A mixture of 6-bromo-N-(4-cyano-2-fluorophenyl)-1 H-indole-3-sulfonamideI-114 (70 mg, 0.18 mmol), 3-pyridylboronic acid (0.22 mmol) andpotassium carbonate (76 mg, 0.55 mmol) was dissolved in dioxane : water(2.5:1, 5.8 mL) and flushed with argon via a septum. Subsequently,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (7 mg) was addedand the reaction mixture was stirred in an argon atmosphere at 95° C.for 16 h.

The mixture was diluted with an aqueous ammonium chloride solution andextracted three times with ethyl acetate. The combined organic layerswere washed with brine, dried over MgSO₄ and concentrated by rotaryevaporation. The crude mixture was purified by column chromatographyeluting with 1% methanol in dichloromethane. It afforded 70 mg ofN-(4-cyano-2-fluorophenyl)-6-(pyridin-3-yl)-1 H-indole-3-sulfonamideI-229 as beige solid.

Yield: 39%.

Neutral LCMS Method 3 (ES⁻F): 393.1 (M+H)⁺, 99% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.24 (s, 1H), 10.83 (s, 1H), 8.86-8.93 (m,1H), 8.55 (d, J=4.5 Hz, 1H), 8.15 (d, J=3.0 Hz, 1H), 8.07 (dt, J=7.9,1.9 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.74-7.76 (m, 1H), 7.73 (dd,J=10.7, 1.6 Hz, 1 H), 7.59 (t, J=8.2 Hz, 1 H), 7.53-7.57 (m, 2H), 7.48(dd, J=7.9, 4.8 Hz, 1H).

The following compounds were synthesized according to Method G:

N-(4-cyano-2-fluorophenyl)-6-(thiophen-3-yl)-1H-i ndole-3-sulfon amide1-230 from 3-thienylboronic acid CAS 6165-69-1, purified with 20% ethylacetate in cyclohexane.

Yield: 69%.

Neutral LCMS Method 3 (ES⁺): 396.0 (M+H)⁺, 95% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.07-12.15 (m, 1H), 10.77 (s, 1H), 8.08 (d,J=3.0 Hz, 1 H), 7.81-7.87 (m, 2H), 7.69-7.74 (m, 2H), 7.61-7.64 (m, 1H), 7.53-7.61 (m, 4H).

N-(4-cyano-2-fluorophenyl)-6-(pyridin-4-yl)-1 H-indole-3-sulfonamideI-231 from 4-pyridylboronic acid CAS 1692-15-5.

Yield: 25%.

Neutral LCMS Method 3 (ES⁺): 393.1 (M+H)⁺, 99% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.28 (d, J=2.4 Hz, 1H), 10.82 (s, 1H), 8.62(d, J=5.5 Hz, 2H), 8.17 (d, J=3.1 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H),7.83-7.85 (m, 1H), 7.70-7.74 (m, 3H), 7.53-7.65 (m, 3H).

N-(4-cyano-2-fluorophenyl)-6-(4-methoxyphenyl)-1H-indole-3-sulfonamideI-232 from (4-methoxyphenyl)boronic acid CAS 5720-07-0, purified with25% ethyl acetate in cyclohexane.

Yield: 24%.

Neutral LCMS Method 3 (ES⁺): 420.1 (M+H)⁺, 97% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.06-12.13 (m, 2H), 10.79 (s, 2H), 8.08 (d,J=2.9 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.72 (d, J=10.1 Hz, 1H),7.52-7.64 (m, 5H), 7.45 (dd, J=8.4, 1.4 Hz, 1 H), 7.02 (d, J=8.8 Hz,2H), 3.79 (s, 3H).

N-(4-cyano-2-fluorophenyl)-6-phenyl-1 H-indole-3-sulfonamide I-233 fromphenylboronic acid CAS 98-80-6, purified with 33% ethyl acetate incyclohexane.

Yield: 57%.

Neutral LCMS Method 3 (ES⁺): 390.1 (M+H)⁺, 95% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.13-12.19 (m, 1H), 10.79 (s, 1H), 8.12 (d,J=3.0 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.72 (dd, J=10.7, 1.8 Hz, 1H),7.64-7.69 (m, 3H), 7.53-7.62 (m, 2H), 7.50 (dd, J=8.4, 1.6 Hz, 1H),7.43-7.48 (m, 2H), 7.32-7.37 (m, 1 H).

N-(4-cyano-2-fluorophenyl)-6-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-indole-3-sulfonamideI-234 from (3,5-dimethylisoxazol-4-yl)boronic acid CAS 16114-47-9,purified with 66% ethyl acetate in petroleum ether.

Yield: 34%.

Neutral LCMS Method 3 (ES⁺): 411.2 (M+H)⁺, 98% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.15 (s, 1H), 10.82 (s, 1H), 8.14 (d, J=3.0Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.73 (d, J=10.8 Hz, 1H), 7.61 (t, J=8.2Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.43 (s, 1H), 7.19 (dd, J=8.3, 1.3 Hz,1H), 2.21 (s, 3H), 2.39 (s, 3H)

N-(4-cyano-2-fluorophenyl)-6-(thiophen-2-yl)-1H-indole-3-sulfonamideI-235 from 2-thienylboronic acid CAS 6165-68-0, purified with 50% ethylacetate in petroleum ether.

Yield: 94%.

Neutral LCMS Method 3 (ES⁺): 398.1 (M+H)⁺, 96% purity.

¹H NMR (500 MHz, DMSO-d₆) δ 12.12 (d, J=2.4 Hz, 1H), 10.82 (s, 1H), 8.11(d, J=3.0 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.73 (dd, J=10.8, 1.5 Hz,1H), 7.67 (d, J=1.0 Hz, 1H), 7.46-7.61 (m, 5H), 7.12 (dd, J=5.1, 3.7 Hz,1H).

N-(4-chloro-2,5-difluorophenyl)-6-(thiophen-3-yl)-1H-indole-3-sulfonamide I-236 from 3-athienylboronic thienylboronic acidCAS 6165-69-1, purified with 33% ethyl acetate in petroleum ether.

Yield: 76%.

Neutral LCMS Method 3 (ES⁺): 425.1 (M+H)⁺, 100% purity.

¹H NMR (600 MHz, DMSO-d₆) δ 12.06 (s, 1H), 10.44 (s, 1H), 8.01 (d, J=3.0Hz, 1H), 7.83 (dd, J=2.9, 1.3 Hz, 1 H), 7.79 (d, J=8.4 Hz, 1H),7.70-7.73 (m, 1 H), 7.63 (dd, J=5.0, 2.9 Hz, 1H), 7.53-7.58 (m, 2H),7.51 (dd, J=9.9, 6.9 Hz, 1H), 7.35 (dd, J=10.5, 7.0 Hz, 1H).

D.7. Synthesis ofN-(4-cyanophenyI)-6-(methylsulfinyl)-1H-indole-3-sulfonamide I-237

Step-1: Synthesis ofN-(4-cyanophenyI)-6-(methylthio)-1H-indole-3-sulfonamide I-237a:

To a solution of 6-bromo-N-(4-cyanophenyI)-1H-indole-3-sulfonamide I-134(0.05 g, 0.13 mmol) in N,N-dimethylacetamide (2 mL) was added Xantphos(0.016 g, 0.03 mmol) and sodium methanethiolate (0.012 g, 0.16 mmol) andthe reaction mixture was purged with argon for 5 min. Pd2(dba)3 (0.02 g,0.03 mmol) was added and the reaction mixture was again purged withargon for 5 min. The reaction mixture was heated in microwave at 180° C.for 30 min. Progress of the reaction was monitored by TLC and LCMS.After completion, the reaction mixture was quenched with saturated NH₄C₁(50 mL) and saturated NaHCO₃ (50 mL) and extracted with EtOAc (20 mL).The organic layer was separated, washed with brine (10 mL), dried overanhydrous Na₂SO₄ and concentrated in vacuum. The crude obtained waspurified by column chromatography (silica, 100-200 mesh, 2% MeOH in DCM)to afford 0.04 g ofN-(4-cyanophenyI)-6-(methylthio)-1H-indole-3-sulfonamide I-237a as anoff-white solid.

Yield: 88%.

Basic LCMS Method 2 (ES⁻): 341.95 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d6) δ 7.14 (d, J=8.80 Hz, 1H) 7.22 (d, J=8.80 Hz,2H) 7.30 (s, 1H) 7.62 (d, J=8.31 Hz, 2H) 7.74 (d, J=8.80 Hz, 1H) 8.08(s, 1H) 10.93 (brs, 1H) 11.99 (brs, 1H) (3H′s merged in solvent peak).

Step-2: Synthesis ofN-(4-cyanophenyI)-6-(methylsulfinyl)-1H-indole-3-sulfonamide I-237

To a solution ofN-(4-cyanophenyI)-6-(methylthio)-1H-indole-3-sulfonamide I-237a (0.12 g,0.34 mmol) in MeOH (14 mL) was added phosphomolybdic acid (0.13 g, 0.07mmol) followed by dropwise addition of H₂O₂ (0.004 mL, 0.34 mmol) at -5°C. The reaction mixture was stirred at -5° C. for 1 h. Progress of thereaction was monitored by TLC and LCMS. After completion, the reactionmixture was quenched with saturated Na₂S₂O₃ (50 mL) solution andsaturated NaHCO₃ (10 mL) solution and extracted with EtOAc (3×50 mL).The organic layer was separated, washed with brine (50 mL), dried overanhydrous Na₂SO₄ and concentrated under vacuum. The crude obtained waspurified by column chromatography (silica, 100-200 mesh, 3% MeOH in DCM)to afford 0.12 g ofN-(4-cyanophenyl)-6-(methylsulfinyl)-1H-indole-3-sulfonamide I-237 aslight brown solid.

Yield: 95%.

Basic LCMS Method 2 (ES⁻): 360 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 2.71 (s, 3H) 7.23 (d, J=8.80 Hz, 2H) 7.45(d, J=8.80 Hz, 1 H) 7.62 (d, J=8.80 Hz, 2H) 7.79 (s, 1 H) 7.97 (s, 1 H)8.31 (brs, 1 H) 11.03 (s, 1 H) 12.41 (brs, 1H).

D.8. Synthesis of6-(methylsulfonyl)-N-(2,2,6-trifluoro-1,3-benzodioxo1-5-yl)-1H-indole-3-sulfonamideI-238

To a solution of6-bromo-N-(2,2,6-trifluoro-1,3-benzodioxo1-5-yl)-1H-indole-3-sulfonamide1-135 (0.18 g, 0.40 mmol) in DMSO (4 mL) was added sodium methanesulfinate (0.18 g, 1.80 mmol) and Cul (0.34 g, 1.78 mmol). The reactionmixture was heated at 130° C. for 16h. Progress of the reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasquenched with H₂O (20 mL) and extracted with EtOAc (30 mL). The organiclayer was separated, washed with brine (100 mL), dried over anhydrousNa₂SO₄ and concentrated in vacuum. The crude obtained was purified bycolumn chromatography (silica, 100-200 mesh, 5% MeOH in DCM) to afford0.022g of6-(methylsulfonyl)-N-(2,2,6-trifluoro-1,3-benzodioxo1-5-yl)-1H-indole-3-sulfonamideI-238 as an off-white solid.

Yield: 12%.

Basic LCMS Method 2 (ES⁻): 447 (M−H)⁻, 96% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.22 (s, 3H) 7.34 (d, J=6.36 Hz, 1 H) 7.44(d, J=8.80 Hz, 1H) 7.71 (dd, J=8.31, 1.47 Hz, 1H) 7.95 (d, J=8.31 Hz,1H) 8.03 (s, 1H) 8.17 (d, J=2.93 Hz, 1H) 10.20 (s, 1H) 12.51 (brs, 1H).

D.9. Synthesis of6-methylsulfonyl-N-(2,4,5-trifluorophenyI)-1H-indole-3-sulfonamide I-239

To a solution of 6-bromo-N-(2,4,5-trifluorophenyl)-1H-indole-3-sulfonamide I-136 (0.40 g, 0.98 mmol) in DMSO (15 mL) wasadded sodium methane sulfinate (0.45 g, 4.41 mmol) and Cul (0.84 g, 4.41mmol). The reaction mixture was heated at 130° C. for 16h. Progress ofthe reaction was monitored by TLC and LCMS. After completion, thereaction mixture was quenched with saturated NH4C1 (30 mL) and saturatedNaHCO₃ (60 mL) solution. The product was extracted with EtOAc (60 mL).The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude obtained was purified byflashcolumn chromatography to afford6-methylsulfonyl-N-(2,4,5-trifluorophenyI)-1H-indole-3-sulfonamide I-239(0.02 g, 5%) as a white solid.

Yield: 5%.

Basic LCMS Method 2 (ES⁻): 403.00 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.22 (s, 3H) 7.31-7.41 (m, 1H) 7.41-7.53 (m,1H) 7.72 (d, J=8.31 Hz, 1H) 7.96 (d, J=8.31 Hz, 1H) 8.04 (s, 1H) 8.22(d, J=2.45 Hz, 1H) 10.34 (s, 1H) 12.54 (brs, 1H).

D.10. Synthesis ofN-(2,2-difluoro-1,3-benzodioxo1-4-yl)-6-methylsulfonyl-1H-indole-3-sulfonamideI-240

To a solution of6-bromo-N-(2,2-difluoro-1,3-benzodioxo1-4-yl)-1H-indole-3-sulfonamideI-137 (0.13 g, 0.30 mmol) in DMSO (4 mL) was added sodium methanesulfinate (0.15 g, 1.50 mmol) and Cul (0.28 g, 1.50 mmol). The reactionmixture was heated at 130° C. for 16h. Progress of the reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasquenched with saturated NH₄C1 (50 mL) and saturated NaHCO₃ (50 mL)solution. The product was extracted with EtOAc (4×50 mL). The organiclayer was separated, washed with brine (2×50 mL), dried over anhydrousNa₂SO₄ and concentrated under vacuum. The crude obtained was purified bycolumn chromatography (silica, 100-200 mesh, 55 to 65% EtOAc in hexanes)to afford 0.032g ofN-(2,2-difluoro-1,3-benzodioxo1-4-yl)-6-methylsulfonyl-1H-indole-3-sulfonamideI-240 as an off-white solid.

Yield: 25%.

Basic LCMS Method 2 (ES⁻): 429.00 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.19 (s, 3H) 6.95 (d, J=8.31 Hz, 1H) 7.07(t, J=8.07 Hz, 1H) 7.11-7.17 (m, 1H) 7.69 (d, J=8.80 Hz, 1H) 7.88 (d,J=8.31 Hz, 1H) 8.03 (s, 1H) 8.22 (d, J=2.45 Hz, 1H) 10.46 (s, 1H) 12.54(brs, 1H).

D.11. Synthesis ofN-(4-azido-2-fluorophenyI)-6-chloro-1H-indole-3-sulfonamide I-241

Step-1: Synthesis ofN-(4-amino-2-fluorophenyl)-6-chloro-1H-indole-3-sulfonamide I-241a:

To a solution of 6-chloro-N-(2-fluoro-4-nitro-phenyl)-1H-indole-3-sulfonamide I-138 (0.32 g, 0.87 mmol) in EtOAc (15 mL) wasadded Pd(OH)₂ (0.10 g) at 0° C. and the reaction mixture was stirred atroom temperature for 3h under hydrogen pressure. Progress of thereaction was monitored by TLC and LCMS. After completion, the reactionmixture was filtered through a celite pad, washed with EtOAc (3×20 mL)and the filtrate was concentrated in vacuum. The crude obtained waswashed with pentane (10 mL) and dried in vacuum to affordN-(4-amino-2-fluorophenyl)-6-chloro-1H-indole-3-sulfonamide 1 -241a(0.33 g crude) as a grey solid.

This compound was used as such for the next reaction without furtherpurification.

Basic LCMS Method 2 (ES⁻): 338.00 (M−H)⁻, 80% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 5.33 (s, 2H) 6.12-6.18 (m, 2H) 6.60 (t,J=8.80 Hz, 1H) 7.16 (d, J=8.40 Hz, 1H) 7.51 (s, 1H) 7.64-7.69 (m, 2H)9.14 (s, 1H) 11.92 (s, 1H).

Step-2: Synthesis of N-(4-azido-2-fluorophenyl)-6-chloro-1H-indole-3-sulfonamide I-241

To a solution ofN-(4-amino-2-fluorophenyl)-6-chloro-1H-indole-3-sulfonamide 1 -241a(0.15 g, 0.44 mmol) in TFA (3 mL) was added NaNO2 (0.12 g, 1.77 mmol)portion wise at 0° C. and the reaction mixture was stirred at sametemperature for 30 min. NaN3 (0.09 g, 1.46 mmol) was added portion wiseat 0° C. and the reaction mixture was stirred at 0° C. for 30 min.Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was poured in to ice-cold H₂O (10 mL)and extracted with EtOAc (2×10 mL). The organic layer was separated,washed with brine (10 mL), dried over anhydrous Na₂SO₄ and concentratedin vacuum. The crude obtained was purified by column chromatography(silica, 100-200 mesh, 30% EtOAc in hexanes) to afford 0.03g ofN-(4-azido-2-fluorophenyl)-6-chloro-1H-indole-3-sulfonamide I-241 as ayellow solid.

Yield: 19%.

Basic LCMS Method 2 (ES⁻): 364.00 (M−H)⁻, 96% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.83-6.99 (m, 2H) 7.16-7.31 (m, 2H) 7.52 (s,1H) 7.68-7.77 (m, 1H) 7.84 (brs, 1H) 9.94 (s, 1H) 12.04 (brs, 1H).

D.12. Synthesis of6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-indole-3-sulfonamideI-250

To a solution of7-bromo-6-chloro-N-(4-chloro-2,5-difluorophenyI)-1H-indole-3-sulfonamideI-249 (0.16 g, 0.35 mmol) and 3,5- dimethylisoxazole-4-boronic acidpinacol ester (0.39 g, 1.73 mmol) in toluene (8 mL) and H₂O (1 mL) wasadded K₃PO₄ (0.22 g, 1.04 mmol). The reaction mixture was purged withargon for 20 min followed by addition of PdCl₂(dppf).DCM (0.03 g, 0.03mmol). The reaction mixture was heated at 100° C. for 16h. Progress ofthe reaction was monitored by TLC and LCMS. After completion, thereaction mixture was diluted with H₂O (100 mL) and extracted with EtOAc(200 mL). The organic layer was separated, dried over anhydrous Na₂SO₄and concentrated under vacuum. The crude obtained was purified byCombi-flash column chromatography (40% EtOAc in hexanes) to afford6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-indole-3-sulfonamide I-250 (0.04 g) as a white solid.

Yield: 24%.

Basic LCMS Method 2 (ES⁻): 470.00 (M−H)⁻, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 1.98 (s, 3H) 2.15 (s, 3H) 7.31-7.38 (m, 1H)7.41 (d, J=8.80 Hz, 1 H) 7.56 (dd, J=9.78, 6.85 Hz, 1 H) 7.85 (d, J=8.80Hz, 1 H) 8.01 (d, J=3.42 Hz, 1H) 10.54 (s, 1H) 12.15 (brs, 1H).

D.13. Synthesis of6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-cyano-1H-indole-3-sulfonamideI-256

To a solution of7-bromo-6-chloro-N-(4-chloro-2,5-difluorophenyI)-1H-indole-3-sulfonamideI-249 (0.13 g, 0.28 mmol) in DMF (9 mL) was added CuCN (0.05 g, 0.56mmol) and the reaction mixture was purged with argon for 20 min.Pd(PPh3)4 (0.03 g, 0.03 mmol) was added and the reaction mixture washeated in microwave at 175° C. for 1 h. Progress of the reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasdiluted with H₂O (100 mL) and EtOAc (100 mL), filtered through celiteand extracted with EtOAc (100 mL). The organic layer was separated,dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crudeobtained was purified by prep HPLC to afford6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-cyano-1H-indole-3-sulfonamideI-256 (0.023 g, 20%) as a white solid.

Yield: 20%.

Basic LCMS Method 2 (ES⁻): 400 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 7.35 (dd, J=10.27, 6.97 Hz, 1H) 7.50-7.56(m, 2H) 8.07 (d, J=8.68Hz, 1H) 8.16 (s, 1H) 10.58 (brs, 1H) 13.2 (brs,1H).

D.14. Synthesis of6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-(methylsulfonyl)-1H-indole-3-sulfonamideI-261

To a solution of7-bromo-6-chloro-N-(4-chloro-2,5-difluorophenyI)-1H-indole-3-sulfonamideI-249 (0.15 g, 0.32 mmol) in DMSO (10 mL) was added Cul (0.25 g, 1.29mmol) and sodium methanesulfonate (0.13 g, 1.29 mmol). The reactionmixture was heated at 130° C. for 6h. Progress of the reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasdiluted with saturated NH₄C1 (35 mL), saturated NaHCO₃ (15 mL) andextracted with EtOAc (2×50 mL). The organic layer was separated, driedover anhydrous Na₂SO₄ and concentrated under vacuum. The crude obtainedwas purified by column chromatography (silica, 100-200 mesh, 40% EtOAcin hexanes) to afford6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-(methylsulfonyl)-1H-indole-3-sulfonamide 1-261 (0.015 g) as an off-white solid.

Yield: 10%.

Basic LCMS Method 2 (ES⁻): 453 (M−H)⁻, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.52 (s, 3H) 7.36-7.40 (m, 1 H) 7.55 (d,J=8.80 Hz, 2H) 7.88 (d, J=3.42 Hz, 1H) 8.10 (d, J=8.80 Hz, 1H) 10.65(brs, 1H) 11.76 (brs, 1H).

D.15. Method H: Synthesis of6-chloro-N-(5-chloro-3,6-difluoropyridin-2-yl)-7-methoxy-1H-indole-3-sulfonamideI-310

Step-1: Synthesis of 6-chloro-7-methoxy-1 H-indole-3-sulfonamide I-310a:

To a solution of 6-chloro-7-methoxy-1 H-indole-3-sulfonyl chlorideXII-25 (170mg, 0.265mmo1) in THF (10 mL), NH₃ gas was purged at 0° C.for 10 min. The reaction mixture was stirred at room temperature for 30min. Progress of the reaction was monitored by TLC. After completion,the reaction mixture was concentrated under vacuum.The crude materialwas washed with DCM: Hexane (1:4, 10 mL) to afford6-chloro-7-methoxy-1H-indole-3-sulfonamide I-310a (150mg) as brownsolid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 78%.

Basic LCMS Method 2 (ES⁻F): 259 (MH)+, 36% purity.

Step-2: Synthesis of6-chloro-N-(5-chloro-3,6-difluoropyridin-2-yl)-7-methoxy-1H-indole-3-sulfonamideI-310:

To a stirred solution of 6-chloro-7-methoxy-1 H-indole-3-sulfonamideI-310a (100mg, 0.384mmo1) and 3-chloro-2,5,6-trifluoro-pyridine (64.3mg,0.384mmo1) in 1,4-Dioxane (10mL), K2CO3 (53mg, 0.384mmo1) was added atRT. The reaction mixture was heated at 100° C. for 8h. Progress of thereaction was monitored by TLC. After completion, the reaction mixturewas filtered through a celite bed. The filtrate was concentrated undervacuo.The crude obtained was purified by column chromatography (silica,100-200 mesh, 10-50% EtOAc in hexanes) to afford 60 mg; which wasre-purified by Prep-TLC using 40% EtOAc in hexane to afford6-chloro-N-(5-chloro-3,6-difluoro-2-pyridyI)-7-methoxy-1H-indole-3-sulfonamideI-310 (14mg) as an off white solid.

Yield: 9%.

Basic LCMS Method 2 (ES⁻): 406 (M−H)⁻, 97% purity. ¹H NMR (400 MHz,DMSO-d₆) δ 3.91 (s, 3 H) 7.25 (d, J=8.80 Hz, 1 H) 7.63 (d, J=8.31 Hz, 1H) 8.10 (br s, 1 H) 8.17-8.24 (m, 1 H) 11.52 (br s, 1 H) 12.58 (brs, 1H).

The following compounds in Table 8 may be synthesized according methodsanalogous to Method H.

TABLE 8 Con- Con- Sulfonyl ditions, Fluoro ditions, Purifi- chloridesTime Yield pyridine Time cation Yield N° XII (Step-1) (%) (Step-2)(Step-2) conditions (%) I- XII-1 DCM, 51 2879- CsCO₃, 30-60% 12 316 16 h42-7 DMF, AcOEt/ 140° C., Heptane mw, 1 h I- XII-10 NH4OH 70 2879-CsCO₃, Basic prep 20 317 ACN, aq, 1 h 42-7 DMF, LCMS 70° C., Method 1 2h

N-(5-chloro-3,6-difluoropyridin-2-yl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamideI-316

Basic LCMS Method 1 (ES⁺): 395 (M+H)⁺, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 13.29 (s, 1H), 11.52 (s, 1H), 8.92 (dd,J=4.3, 1.7 Hz, 1H), 8.45 (dd, J=8.2, 1.7 Hz, 1H), 8.23-8.03 (m, 3H),7.72 (d, J=8.8 Hz, 1 H), 7.58 (dd, J=8.2, 4.3 Hz, 1H).

N-(5-chloro-3,6-difluoropyridin-2-yl)-1,6,7,8-tetrahydrocyclopenta[g]indole-3-sulfonamideI-317

Basic LCMS Method 1 (ES⁺): 384 (M+H)⁺, 93% purity.

D.16. Synthesis ofN-(4-chloro-2,5-difluorophenyI)-2-fluoro-6-methoxy-1H-indole-3-sulfonamideI-318

Step-1: Synthesis ofN-(4-chloro-2,5-difluorophenyl)-6-methoxy-1-(phenylsulfonyl)-1H-indole-3-sulfonamideI-318a

Indole XII-22 (1.348 g, 3.49 mmol) and 4-chloro-2,5-difluoroaniline (569mg, 3.48 mmol) were heated 1 h in pyridine (5 mL) at 80° C. The oilyresidue was diluted with ethyl acetate, washed twice with brine, driedover magnesium sulfate and evaporated to dryness. The crude residue wasthen dissolved in methanol (150 mL) and refluxed to dissolve most of theproduct. The solution was then evaporated to ca. 50 mL. After cooling tort the precipitate was filtered. It was then taken up in dichloromethane(12 mL), sonicated, and filtered again to afford the desired productI-318a (763 mg) as an off-white solid. Purification of the mother watersby flash chromatography (SiO2, dichloromethane) yielded additional 273mg of desired product I-318a

Yield: 58%

Neutral LCMS Method 3 (ES⁺): 512.9 (M+H)⁺, 97% purity.

¹H NMR (600 MHz, CDCl₃) δ: 8.03 (s, 1H), 7.84 (d, J=7.5 Hz, 2H), 7.63(t, J=7.5 Hz, 1 H), 7.58 (d, J=8.8 Hz, 1H), 7.49 (t, J=7.8 Hz, 2H), 7.46(d, J=2.2 Hz, 1 H), 7.43 (dd, J =9.6, 6.8 Hz, 1 H), 7.06 (br s, 1 H,NH), 6.97-6.92 (m, 2H), 3.87 (s, 3H).

Step-2: Synthesis ofN-(4-chloro-2,5-difluorophenyl)-6-methoxy-N-(methoxymethyl)-1-(phenylsulfonyl)-1H-indole-3-sulfonamide1-318b

I-318a (200 mg, 0.39 mmol) and sodium hydride (60% dispersion in mineraloil, 19 mg, 0.47 mmol) were placed in dry dimethylformamide (2.5 mL)under argon atmosphere. The solution was stirred at rt for 15 min, thenbromomethyl methyl ether (36 pL, 0.47 mmol) in dry DMF (1.5 mL) wasadded and the solution was stirred at rt for 2.5 h. The reaction mixturewas quenched with water, extracted three times with ethyl acetate,washed with brine, dried over magnesium sulfate and evaporated todryness. The crude residue was purified by flash chromatography (SiO₂,CombiFlash, 10% to 20% AcOEt in Petroleum Ether) to afford the desiredproduct I-318b (187 mg) as a colorless oil.

Yield: 86% ¹H NMR (600 MHz, CDCl₃) 6: 7.92-7.86 (m, 3H), 7.65 (t, J=7.7Hz, 1 H), 7.52 (t, J=7.9 Hz, 2H), 7.49 (s, 1H), 7.42 (d, J=9.1 Hz, 1H),7.12 (dd, J=8.7, 6.3 Hz, 1H), 7.02 (dd, J=9.0, 6.4 Hz, 1H), 6.93 (dd,J=8.7, 2.4 Hz, 1H), 5.01 (d, J=2.2 Hz, 2H), 3.89 (d, J=2.1 Hz, 3H), 3.42(d, J=2.1 Hz, 3H).

Neutral LCMS Method 3 (ES⁺): 574.1 (M+NH4)+, 98% purity.

Step-3: Synthesis ofN-(4-chloro-2,5-difluorophenyl)-2-fluoro-6-methoxy-N-(methoxymethyl)-1-(phenylsulfonyl)-1H-indole-3-sulfonamideI-318c

I-318b (160 mg, 0.287 mmol) was placed in a flask in dry tetrahydrofuran(1.5 mL) under argon atmosphere, and the solution was cooled to -78° C.Then lithium diisopropylamide was freshly prepared by adding dropwisen-Buli (1.6 M in hexanes, 341 μL 0.545 mmol) at -78° C. to a solution ofdiisopropylamine (81 μL, 0.574 mmol) in dry tetrahydrofuran (2 mL) Thissolution was then added dropwise to the reaction mixture, that wassubsequently stirred at −78° C. for 50 min. N-Fluorobenzenesulfonimide(136 mg, 0.430 mmol) in dry tetrahydrofuran (2 mL) was then added andthe reaction mixture was allowed to slowly reach room temperatureovernight. The solution was then quenched with water, extracted threetimes with dichloromethane, washed with brine, dried over magnesiumsulfate and evaporated to dryness. The crude residue was purified byflash chromatography (SiO₂, CombiFlash, 10% to 20% AcOEt in PetroleumEther) to afford the desired product 1-318c, in a mixture with thestarting material I-318b (ratio ca. 1:3, 66 mg), as a light yellow oil.

This compound was used as such for the next reaction without additionalpurification.

Neutral LCMS Method 3 (ES⁺): 592.0 (M+NH₄)+.

Step-4: Synthesis ofN-(4-chloro-2,5-difluorophenyl)-2-fluoro-6-methoxy-N-(methoxymethyl)-1H-indole-3-sulfonamideI-318d

I-318c (in a mixture with I-318b ratio ca. 1:3, 60 mg, ca. 0.13 mmol)and potassium carbonate (73 mg, 0.525 mmol) were placed in dioxane (2mL) and water (1 mL) and stirred for 4 h at 70° C. Then the reactionmixture was treated with 0.1 M hydrochloric acid aqueous solution (4mL), extracted twice with ethyl acetate, washed with brine, evaporatedto dryness and dried over magnesium sulfate to afford the desiredcompound I-318d, in a mixture with the corresponding non-fluorinatedcompound (ratio ca. 1:3, 39 mg), as a light green solid.

This compound was used as such for the next reaction without furtherpurification.

Neutral LCMS Method 3 (ES⁺): 452.1 (M+NH₄)+.

Step-5: Synthesis ofN-(4-chloro-2,5-difluorophenyl)-2-fluoro-6-methoxy-1H-indole-3-sulfonamideI-318

I-318d (in a mixture with the corresponding non-fluorinated compound,ratio ca. 1:3, 39 mg, ca. 0.09 mmol) was placed in a solution ofhydrogen chlorid 4 M in dioxane (2 mL) and was refluxed overnight. Thereaction mixture was then quenched with saturated hydrogen sodiumcarbonate aqueous solution, extracted three times with dichloromethane,washed with brine, dried over magnesium sulfate and evaporated todryness. The crude residue was purified by preparative HPLC (Basic prepLCMS Method 1) to afford the pure desired product 1-318 (4 mg)

Yield: 7% (2 steps)

Basic LCMS Method 1 (ES⁻): 389 (m-H)-, 100% purity.

D.17. Synthesis of ethyl3-(6-{[(6-chloro-1H-indo1-3-yl)sulfonyl]amino}-2,5-difluoropyridin-3-yl)propanoate1-331

Step-1: Synthesis of ethyl(2E)-3-(6-{[(6-chloro-1H-indo1-3-yl)sulfonyl]amino}-2,5-difluoropyridin-3-yl)prop-2-enoate1-330

A mixture ofN-(5-bromo-3,6-difluoropyridin-2-yl)-6-chloro-1H-indole-3-sulfonamideI-245 (100 mg, 0.24 mmol), 2- ethoxycarbonylvinylboronic acid pinacolester (64mg, 0.28 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (19 mg,0.024mmo1), cesium fluoride (72mg, 0.47mmo1) and potassium carbonate (99mg, 0.71 mmol) was dissolved in dioxane : water (3:1, 2 mL) and flushedwith argon via a septum. Subsequently, the reaction mixture was stirredat 120° C. for 20 min in a microwave. The mixture was diluted with waterand extracted twice with ethyl acetate. The combined organic layers weredried over MgSO₄ and concentrated by rotary evaporation. The crudemixture was purified by preparative HPLC (Basic prep LCMS Method 1). Itafforded 68 mg of ethyl(2E)-3-(6-{[(6-chloro-1H-indo1-3-yl)sulfonyl]amino}-2,5-difluoropyridin-3-yl)prop-2-enoate1-330 as a beige solid.

Yield: 65%.

Basic LCMS Method 1 (ES⁻): 440 (M−H)⁻, 98% purity.

Step-2: Synthesis of ethyl3-(6-{[(6-chloro-1H-indo1-3-yl)sulfonyl]amino}-2,5-difluoropyridin-3-yl)propanoate1-331

To a solution of ethyl(2E)-3-(6-{[(6-chloro-1H-indo1-3-yl)sulfonyl]amino}-2,5-difluoropyridin-3-yl)prop-2-enoate1-330 (0.65 g, 3.26 mmol) in EtOH (1.5 mL) was added Pt/C (6 mg) and thereaction mixture was stirred at room temperature for 16h under hydrogenpressure (3.5 bar). After completion, the reaction mixture was filteredthrough a celite pad and the filtrate was concentrated under vacuum. Thecrude mixture was purified by two successive preparative HPLC (basic andacidic) to afford 4mg of3-(6-{[(6-chloro-1H-indo1-3-yl)sulfonyl]amino}-2,5-difluoropyridin-3-yl)propanoate1-331 as a white solid.

Yield: 6%.

Basic LCMS Method 1 (ES⁻): 442 (M−H)⁻, 97% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 1H), 11.06 (s, 1H), 8.09 (d, J=2.7Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.75 (t, J=8.6 Hz, 1H), 7.54 (d, J=1.9Hz, 1H), 7.22 (dd, J=8.6, 1.9 Hz, 1 H), 3.99 (q, J=7.1 Hz, 2H),2.75-2.52 (m, 4H), 1.08 (t, J=7.1 Hz, 3H).

D.18. Synthesis of6-chloro-N-[5-(2-ethoxyethyl)-3,6-difluoropyridin-2-yl]-1H-indole-3-sulfonamide I-333

Step-1: Synthesis of6-chloro-N-{5-[(E)-2-ethoxyethenyl]-3,6-difluoropyridin-2-yl}-1H-indole-3-sulfonamideI-332

A mixture ofN-(5-bromo-3,6-difluoropyridin-2-yl)-6-chloro-1H-indole-3-sulfonamideI-245 (100 mg, 0.24 mmol), (E)-1-ethoxyethene-2-boronic acid pinacolester (58mg, 0.28 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (19 mg,0.024mmo1) and potassium carbonate (99 mg, 0.71 mmol) was dissolved indioxane : water (3:1, 2 mL) and flushed with argon via a septum.Subsequently, the reaction mixture was stirred at 120° C. for 20 min ina microwave. The mixture was diluted with water and extracted twice withethyl acetate. The combined organic layers were dried over MgSO₄ andconcentrated by rotary evaporation. The crude mixture was purified bypreparative HPLC (Basic prep LCMS Method 1). It afforded 25 mg of6-chloro-N-{5-[(E)-2-ethoxyethenyl]-3,6-difluoropyridin-2-yl}-1H-indole-3-sulfonamide I-332 as a beige solid.

Yield: 26%.

Basic LCMS Method 1 (ES⁻): 412 (M−H)⁻, 94% purity.

Step-2: Synthesis of6-chloro-N-[5-(2-ethoxyethyl)-3,6-difluoropyridin-2-yl]-1H-indole-3-sulfonamide1-333

To a solution of6-chloro-N-{5-[(E)-2-ethoxyethenyl]-3,6-difluoropyridin-2-yl}-1H-indole-3-sulfonamide1-332 (0.20 g, 0.05 mmol) in EtOH (0.5 mL) was added Pt/C (15 mg) andthe reaction mixture was stirred at 50° C. for 16h under hydrogenpressure (4bar). After completion, the reaction mixture was filteredthrough a celite pad and the filtrate was concentrated under vacuum. Thecrude mixture was purified by preparative HPLC (Basic prep LCMSMethod 1) to afford 10mg of6-chloro-N-[5-(2-ethoxyethyl)-3,6-difluoropyridin-2-yl]-1H-indole-3-sulfonamideI-333 as a white solid.

Yield: 50%.

Basic LCMS Method 1 (ES⁻): 414 (m-H)-, 98% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 1H), 11.05 (s, 1H), 8.09 (d, J=2.9Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.73 (t, J=8.7 Hz, 1H), 7.54 (d, J=1.9Hz, 1H), 7.23 (dd, J =8.6, 1.9 Hz, 1H), 3.50 (t, J=6.5 Hz, 2H), 3.40 (d,J=6.9 Hz, 2H), 2.67 (t, J=6.5 Hz, 2H), 1.04 (t, J=7.0 Hz, 3H).

D.19. Synthesis of6-azido-N-(4-cyano-2-fluorophenyI)-1H-indole-3-sulfonamide I-335

Step-1: Synthesis of 6-amino-N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide I-335a:

To a solution of6-nitro-N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide I-334 (0.50g, 1.37 mmol) in MeOH (20 mL) was added Pd/C (0.10 g, 1.02 mmol). Thereaction mixture was stirred at room temperature for 3h under hydrogenpressure. Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was filtered through celite and thefiltrate was concentrated under vacuum to afford6-amino-N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide I-335a (0.40g) as a pale yellow solid.

This compound was used as such for the next reaction without furtherpurification. Yield: 90%.

Basic LCMS Method 2 (ES⁻F): 331 (M+H)⁺, 83% purity. Step-2: Synthesis of6-azido-N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide I-335:

To a solution of 6-amino-N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide I-335a (0.20 g, 0.50 mmol) in TFA (5 mL) wasadded NaNO₂ (0.14 g, 2.02 mmol) at 0° C. and the reaction mixture wasstirred at same temperature for 30 min. NaN₃ (0.11 g, 1.77 mmol) wasadded at 0° C. and the reaction mixture was stirred at same temperaturefor 30 min. Progress of the reaction was monitored by TLC and LCMS.After completion, the reaction mixture was diluted with H₂O (150 mL) andextracted with EtOAc (200 mL). The organic layer was separated, washedwith brine (100 mL), dried over anhydrous Na₂SO₄ and concentrated undervacuum. The crude obtained was purified by combi-flash columnchromatography (25% EtOAc in hexanes) to afford6-azido-N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide I-335 (0.06g, 31%) as a yellow solid.

Yield: 31%.

Basic LCMS Method 2 (ES⁻): 355 (M−H)⁻, 93% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 6.99 (dd, J=8.00 Hz, 2.00 Hz, 1H) 7.17 (d,J=2.00 Hz, 1H) 7.54-7.59 (m, 2H) 7.74 (d, J=10.0 Hz, 1H) 7.84 (d, J=8.80Hz, 1H) 8.07 (d, J=2.80 Hz, 1H) 10.80 (brs, 1H) 12.06 (brs, 1H).

D.20. Synthesis of6-chloro-N-(5-ethyl-3,6-difluoropyridin-2-yl)-1H-indole-3-sulfonamide1-338

Step-1: Synthesis of6-chloro-N-{5-[(E)-2-ethoxyethenyl]-3,6-difluoropyridin-2-yl}-1H-indole-3-sulfonamide I-332

A mixture ofN-(5-bromo-3,6-difluoropyridin-2-yl)-6-chloro-1H-indole-3-sulfonamideI-245 (150 mg, 0.35 mmol), vinylboronic acid pinacol ester (69mg, 0.42mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (29 mg,0.035 mmol) and potassium carbonate (149 mg, 1.06 mmol) was dissolved indioxane : water (3:1, 3 mL) and flushed with argon via a septum.Subsequently, the reaction mixture was stirred at 120 ° C. for 40 min ina microwave. The mixture was diluted with water and extracted twice withethyl acetate. The combined organic layers were dried over MgSO₄ andconcentrated under vacuum. The crude mixture was purified by preparativeHPLC (Basic prep LCMS Method 1). It afforded 21 mg of6-chloro-N-(5-ethenyl-3,6-difluoropyridin-2-yl)-1 H-indole-3-sulfonmide1-337 as a beige solid.

Yield: 11%.

Basic LCMS Method 1 (ES⁻): 368 (M−H)⁻, 90% purity.

Step-2: Synthesis of6-chloro-N-(5-ethyl-3,6-difluoropyridin-2-yl)-1H-indole-3-sulfonamide1-338

To a solution of6-chloro-N-(5-ethenyl-3,6-difluoropyridin-2-yl)-1H-indole-3-sulfonamideI-337 (85 mg, 0.17 mmol) in EtOH (1.7 mL) was added Pt/C (17 mg) and thereaction mixture was stirred at room temperature for 16h under hydrogenpressure (3.5 bar). After completion, the reaction mixture was filteredthrough a celite pad and the filtrate was concentrated under vacuum. Thecrude mixture was purified by preparative HPLC (Basic prep LCMSMethod 1) to afford 9mg of6-chloro-N-(5-ethyl-3,6-difluoropyridin-2-yl)-1 H-indole-3-sulfonamideI-338 as a white solid.

Yield: 14%.

Basic LCMS Method 1 (ES⁻): 370 (M−H)⁻, 99% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 1H), 10.99 (s, 1H), 8.08 (s, 1H),7.85 (s, 1H), 7.73 (s, 1H), 7.55 (d, J=5.5 Hz, 1H), 7.23 (d, J=7.7 Hz,1H), 2.47 (t, 2H), 1.09 (d, J=7.3 Hz, 3H).

D.21. Synthesis of6-azido-N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamideI-353

Step-1: Synthesis of6-amino-N-[45-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamideI-352:

To a solution ofN-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-6-nitro-1H-indole-3-sulfonamide1-351 (0.32 g, 0.69 mmol) in MeOH (20 mL) was added 10% Pd/C (0.30 g,2.82 mmol) and the reaction mixture was stirred at room temperature for1 h under hydrogen pressure. Progress of reaction was monitored by TLCand LCMS. After completion, the reaction mixture was filtered through apad of Celite®, washed with MeOH (3×15 mL) and filtrate was concentratedunder vacuum to afford6-amino-N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamideI-352 (0.241 g) as a pale brown solid.

This compound was used as such for the next reaction without furtherpurification.

Yield: 74%.

Basic LCMS Method 2 (ES⁺): 376 (M+H)⁺, 79% purity. Step-2: Synthesis of6-azido-N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide I-353:

To a solution of6-amino-N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamide1-352 (0.03 g, 0.06 mmol) in TFA (2 mL) was added NaNO₂ (0.02 g, 0.25mmol) at 0° C. and the reaction mixture was stirred at same temperaturefor 30 min. NaN₃ (0.01 g, 0.22 mmol) was added at 0° C. and the reactionmixture was stirred at same temperature for 30 min. Progress of reactionwas monitored by TLC and LCMS. After completion, the reaction mixturewas diluted with H₂O (40 mL) and extracted with EtOAc (2×30 mL). Theorganic layer was separated, washed with brine (20 mL), dried overanhydrous Na₂SO₄ and concentrated under vacuum. The reaction wasrepeated on 0.20 g and the crude obtained from 2 reactions was blendedin EtOAc (20 mL) and concentrated under vacuum. The crude obtained waspurified by combi-flash column chromatography (25% EtOAc in hexanes) toafford6-azido-N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamideI-353 (0.032 g) as a pale brown solid

Yield: 13%.

Basic LCMS Method 2 (ES⁻): 400 (M−H)⁻, 96% purity.

¹H NMR (400 MHz, DMSO-d₆) δ 3.63 (s, 3H) 3.70 (s, 2H) 6.97 (d, J=8.03Hz, 1 H) 7.20 (s, 1H) 7.62 (d, J=9.54 Hz, 1H) 7.87 (d, J=8.28 Hz, 1H)8.12 (s, 1H) 11.03 (brs, 1H) 11.97 (brs, 1H).

D.22. Synthesis of ethyl2-(6-{[(6-chloro-1H-indo1-3-yl)sulfonyl]amino}-2,5-difluoropyridin-3-yl)cyclopropanecarboxylateI-359

Trimethylsulfoxonium iodide (66.75 mg, 0.30 mmol) and sodium hydride(11.59 mg, 0.29 mmol) were mixed in dimethyl sulfoxide (1.0 ml). Thereaction mixture was stirred until a limpid colorless solution wasobtained. Ethyl(2E)-3-(6-{[(6-chloro-1H-indo1-3-yl)sulfonyl]amino}-2,5-difluoropyridin-3-ypprop-2-enoate1-330 (100 mg, 0. 23 mmol) was then added and the reaction mixture wasstirred at room temperature for 20 minutes then heated at 50° C.overnight. A new colorless solution of mixed trimethylsulfoxonium iodide(66.75 mg, 0.30 mmol) and sodium hydride (11.59 mg, 0.29 mmol) indimethyl sulfoxide (1.0 mL) was added to the reaction mixture andheating was maintained at 50° C. for 3 hours. The reaction mixture wasdiluted by water and extracted three times with ethyl acetate. Theorganic layer was dried on magnesium sulfate, concentrated under vacuumand the crude compound was purified by chromatography (PreparativeTLC-elution with dichloromethane/MeOH-95/5) to afford 12 mg of ethyl2-(6-{[(6-chloro-1H-indo1-3-yl)sulfonyl]amino}-2,5-difluoropyridin-3-ypcyclopropanecarboxylateI-359, as a yellow solid.

Yield: 10%.

Basic LCMS Method 1 (ES⁺): 456 (M-FH)+, 88% purity.

Additional examples in Table 9 were prepared following previouslydescribed methods:

TABLE 9 IUPAC Name Structure 6-chloro-N-(3,6- difluoro-5-methylpyridin-2- yl)-1H- pyrrolo[2,3- b]pyridine-3- sulfonamide

1-368 N-(5-bromo-3- fluoropyridin-2- yl)-6-chloro-1H- indole-3-sulfonamide

1-369 6-chloro-N-(3,5- difluoro-6- methoxypyridin-2- yl)-7-(trifluoromethyl)- 1H-indole-3- sulfonamide

1-370 N-(4-bromo-2,5- difluorophenyl)-6- (methylsulfinyl)- 1H-indole-3-sulfonamide

1-371 N-(2,5-difluoro-4- methylphenyl)-6- (methylsulfinyl)- 1H-indole-3-sulfonamide

1-372 N-[4- (difluoromethoxy)- 2,5- difluorophenyl]-6- (methylsulfinyl)-1H-indole-3- sulfonamide

1-373 N-(5-chloro-3- fluoropyridin-2- yl)-1H- pyrrolo[3,2-h]quinoline-3- sulfonamide

1-374

Examples were tested and activities in Ca²+and cAMP assays are reportedin the Table 10 further below.

B. BIOLOGY/PHARMACOLOGY: B-I. Cell cultures

GPR17 Recombinant cell line:

Flp-In T-REx CHO cells stably expressing human GPR17 receptor (CHOhGPR17) from Evi Kostenis' lab (Bonn University, Germany) were culturedat 37° C. in a humidified atmosphere of 5% CO₂. Cells were grown in DMEMwith Nutrient Mixture F-12 supplemented with hygromycin B (500 pg/mL)and blasticidin (30 pg/mL). Expression from the Flp-In locus was inducedby treatment with doxycycline (1 pg/mL) for 16-20 h prior assays.

Primary oligodendrocytes:

Primary oligodendrocyte progenitor cells (OPCs) were isolated from theforebrains of

Wistar rat pups at postnatal day 0 to 2. Cerebra were mechanicallydissociated with a syringe and two different hollow needles (first1.2×40 and then 0.60×30). Clump-free cell suspension was filteredthrough a 70-pm cell strainer and plated into poly-D-lysine-coated75-cm² culture flasks in DMEM supplemented with 10% (v/v)heat-inactivated fetal calf serum, penicillin (100 units/mL), andstreptomycin (0.1 mg/mL) with medium exchanged every second day. After 8to 11 days at 37° C. in a humidified atmosphere of 5% CO₂, mixedcultures were shaken at 240 rpm for 14-24 h to detach OPCs fromastrocytes and microglia. To further enrich for OPCs, the suspension wasplated onto uncoated Petri dishes for 45 min. Then, OPCs were seededinto poly-L-ornithine-coated plates and maintained at 37° C. in ahumidified atmosphere of 5% CO₂ in proliferating

Neurobasal medium supplemented with 2% (v/v) B27, 2 mM GlutaMAX, 100units/mL penicillin, 0.1 mg/mL streptomycin, 10 ng/mL PDGF-AA, and 10ng/mL basic FGF changing the medium every second day.

B-II: Functional in vitro GPR17 assays B-II-1: Calcium mobilizationfunctional assay

GPR17 is a G-protein coupled receptor. GPR17 activation triggers Gq-typeG-protein signaling resulting in endoplasmic reticulum calcium (Ca²⁺)stores release in cytosol which can be measured using Calcium 5 dye, afluorescent indicator dye of cytosolic Ca²+levels. All Examples weretested in GPR17 Ca²⁺ assay to determine (screen) their GPR17 modulatingactivity.

Description of Ca^(2+ assay:)

CHO hGPR17 were defrosted and seeded at a density of 20,000 cells perwell into black 384-well plates with clear bottom. Cells were incubatedovernight at 37° C. in a humidified atmosphere of 5% CO₂. Sixteen totwenty hours after seeding, CHO hGPR17 were loaded for 60 min withCalcium 5 dye, a cytosolic Ca²⁺ indicator fluorescent dye, according tomanufacturer's instructions. Fluorescent signal relative to cytosolicCa²⁺ concentration was recorded over time at room temperature in FLIPRTetra reader. Cells were first incubated for 30 minutes at roomtemperature in HBSS Hepes buffer pH 7.4 containing increasingconcentrations of test compounds (typically 10⁻¹¹M to 10⁻⁶M). Then, 50nM MDL29,951, a GPR17 agonist, was added to the cells. Inhibitoryeffects of varying concentrations test compounds were measured andresulting pIC₅₀s were determined. All incubations were performed induplicate and results were compared to a concentration response curve ofGPR17 agonist and antagonist reference compounds. Analysis and curvefitting were performed in ActivityBase XE using XLfit 4-parameterlogistic equation y=A+((B−A)/(1+((C/x){circumflex over ( )}D))) where A,B, C and D stand for minimum y, maximum y, IC₅₀ and slope, respectively.

Results of Ca²⁺ assay:

When tested in Ca²⁺ mobilization assay, compounds of the Examplespreferably exhibit values of pl C50 greater than or equal to 6.5; morepreferably greater than or equal to 7.5, and even more preferablygreater than or equal to 8.5. The activities of the Example compoundstested are depicted in the table in Section B2B below. The activityranges A, B and C refer to p1050 values in the Ca²⁺ assay as follows:“A”: plC₅₀<7.5, “B”: plC₅₀7.521 ×≤8.5, “C”: plC₅₀>8.5

B-IIB. cAMP accumulation functional assay

GPR17 activation can also recruit Gi-type G-protein signaling, resultingin a decrease of intracellular cyclic adenosine monophosphate (cAMP).Intracellular cAMP changes can be measured using the HTRF cAMP dynamicassay kit from CisBio (Codolet, France). Using homogenous time-resolvedfluorescence technology (HTRF), the assay is based on competitionbetween native cAMP produced by cells and cAMP labelled with the dye d2.The tracer binding was determined by an anti-cAMP antibody labeled withcryptate.

Representative compounds which were active in the Ca²⁺ assay were alsotested in this GPR17 cAMP assay. This was done as a confirmation testwith some representative Examples but not with all compounds of thepresent invention.

Description of cAMP assay

CHO hGPR17 were detached with PBS containing EDTA and dispatched inblack 384-well plates with 5,000 cells per well. Cells were firstincubated for 30 minutes at room temperature in HBSS Hepes (pH 7.4)containing vehicle or varying concentrations of test GPR17antagonist/inverse agonist compounds. Then, a dose response curve ofMDL29,951 GPR17 agonist (typically from 10⁻⁵M to 10⁻¹⁰M) was added onvehicle and on each test GPR17 antagonist/inverse agonist compoundconcentration in a final volume of 20 μL HBSS Hepes buffer (pH 7.4)containing 1% DMSO, 5 μM forskolin and 0.1 mM IBMX. After 60 minutesincubation at room temperature, the reaction is terminated and the cellslysed by adding the d2 detection reagent and the cryptate reagent in 10μL lysis buffer each according to manufacturer's instructions. After 60minutes incubation, changes in cAMP concentrations are measuredaccording to manufacturer's instructions using an Envision plate readerwith laser excitation. All incubations were performed in duplicate. Datawas analyzed using Graph Pad Prism software using the 4-parameterlogistic equation to measure MDL29,951 pEC₅₀s in absence and presence ofGPR17 antagonist/inverse agonist test compounds. Dose ratio (DR) wereplotted against antagonist concentrations and Schild analysis providedestimated affinity pA₂ of GPR17 antagonist/inverse agonist testcompounds.

Results of cAMP assay:

When tested in cAMP assay, compounds of the Examples typically exhibitvalues of pA₂ greater than or equal to 6.5; preferably greater than orequal to 7.5; more preferably greater than or equal to 8.5. Theactivities of the Example compounds tested are depicted in the tablebelow. The activity ranges A, B and C refer to pA₂ values in the cAMPassay as follows: “A”: pA₂ <7.5, “B”: pA₂ 7.5<×≤8.5, “C”: pA₂>8.5.

The following table 10 shows the plC₅₀ and pA₂ values of the Examplecompounds tested in the Ca₂₊, and the cAMP assay. Blanks in the pA₂column indicate that the respective compounds was not yet tested, orthat the result was not yet available.

TABLE 10 Ca²⁺ cAMP Ca²⁺ cAMP Ca²⁺ cAMP Ex assay assay Ex assay assay Exassay assay N° pIC₅₀ pA₂ N° pIC₅₀ pA₂ N° pIC₅₀ pA₂ I-99 A I-160 C B I-1A A I-92 A A I-154 C B I-80 C B I-91 A A I-153 C B I-78 C B I-90 A AI-152 C C I-25 C B I-89 A I-151 C C I-228 C C I-87 A I-150 B C I-227 C CI-86 A I-148 C I-213 C C I-84 A I-143 C C I-202 C B I-82 A I-142 C CI-194 C C I-81 A I-140 C C I-193 C C I-8 A A I-134 C C I-192 C I-77 AI-133 C B I-190 C I-76 A A I-12 C B I-189 C C I-75 A I-118 C C I-188 C CI-74 A I-116 C C I-185 C C I-72 A I-114 C C I-184 C C I-71 A I-110 C CI-183 C C I-70 A I-109 C B I-182 C B I-7 A I-104 C C I-179 C B I-69 A AI-157 B I-177 C C I-68 A I-155 B C I-170 C C I-64 A I-149 B I-165 C I-63A B I-147 B B I-67 B B I-62 A I-145 B I-66 B B I-61 A I-144 B I-65 B BI-60 A A I-141 B C I-55 B B I-6 A I-14 B B I-50 B B I-59 A A I-139 B AI-48 B B I-58 A I-132 B B I-4 A B I-57 A I-129 B B I-39 B A I-56 A BI-127 B B I-241 B B I-54 A I-126 B B I-242 B C I-53 A I-125 B B I-238 BB I-52 A B I-124 B B I-235 B C I-51 A I-123 B B I-233 B A I-5 A I-119 BB I-230 B B I-49 A B I-113 B A I-229 B B I-47 A I-112 B B I-224 B B I-46A I-108 B B I-223 B A I-45 A I-107 B B I-221 B B I-44 A B I-102 B I-220B B I-43 A I-212 B C I-219 B B I-42 A I-210 B C I-216 B B I-41 A I-206 BC I-215 B B I-40 A I-204 B C I-196 A I-38 A I-203 B C I-19 A I-37 A I-20B I-180 A I-36 A I-199 B C I-175 A B I-35 A I-195 B C I-171 A I-34 AI-191 B C I-17 A I-33 A I-187 B I-169 A I-32 A I-186 B B I-166 A I-31 AI-181 B B I-164 A I-30 A I-18 B I-163 A I-3 A I-178 B B I-16 A I-29 AI-176 B I-158 A I-28 A I-174 B B I-156 A I-27 A I-173 B B I-15 A I-26 AI-172 B I-146 A I-240 A A I-168 B I-131 A I-24 A A I-167 B I-130 A I-239A A I-161 B I-13 A I-237 A A I-159 B B I-128 A I-236 A A I-117 A I-122 AI-234 A I-115 A I-121 A I-232 A I-111 A I-120 A I-231 A I-11 A I-197 AI-23 A I-106 A I-85 B B I-226 A A I-105 A I-83 B B I-225 A B I-103 AI-79 B A I-222 A I-101 A I-73 B C I-22 A I-100 A B I-201 A C I-218 AI-10 A I-200 B B I-217 A I-98 B B I-2 A I-214 A I-97 B B I-198 B B I-211A I-96 B A I-207 A I-21 A I-95 B B I-205 A I-209 A I-94 B B I-9 B BI-208 A B I-93 B B I-88 B B I-162 C C I-243 B B I-244 B C I-245 C CI-246 C C I-247 B C I-248 B B I-250 B B I-251 B B I-252 C C I-253 C CI-254 C C I-255 C C I-256 C C I-257 C C I-258 C B I-259 B C I-260 B BI-261 B B I-262 B C I-263 B B I-264 A A I-265 B A I-266 C C I-267 C CI-268 C C I-269 C C I-270 C C I-271 C C I-272 B C I-273 B B I-274 B BI-275 B B I-276 B B I-277 B C I-278 B C I-279 B B I-280 B B I-281 B BI-282 B B I-283 B B I-284 B A I-285 C C I-286 C C I-287 C B I-288 C BI-289 C C I-290 C C I-291 C C I-292 B B I-293 B B I-294 B B I-295 B BI-296 B B I-297 B C I-298 B B I-299 B C I-300 B B I-301 B B I-302 B BI-303 C C I-304 C C I-305 C C I-306 B C I-307 B B I-308 C C I-309 C CI-310 C C I-311 B B I-312 B B I-313 B B I-314 B B I-315 C C I-316 B BI-317 B B I-318 B B I-319 C C I-320 C I-321 C C I-322 C I-323 C C I-324C C I-325 C C I-326 B C I-327 C C I-328 C C I-329 C C I-330 B C I-331 CC I-332 B C I-333 C C I-335 B B I-336 C B I-337 B C I-338 C C I-339 C BI-340 B B I-341 C C I-342 B B I-343 B C I-344 B B I-345 B B I-346 B BI-347 B C I-348 C B I-349 C C I-350 C C I-351 B B I-352 B B I-353 C CI-354 C C I-355 C B I-356 B B I-357 B B I-358 B B I-359 B B I-360 C CI-361 C C I-362 B C I-363 B B I-364 C C I-365 B B I-366 B B

BAC: Oligodendrocyte Maturation/Myelination Assays

The effects of negative modulators of GPR17 on primary oligodendrocytesmaturation/myelination can be assessed in vitro by immunoassays usingantibodies directed against Myelin Basic Protein (MBP), as marker formature oligodendrocytes.

Description of MBP Western Blot/Oligodendrocyte/Myelination Assay

After 3-4 days in proliferation medium, rat primary OPCs were seeded at25,000 cells per cm² in 12-well tissue culture plates and switched togrowth factor-free Neurobasal medium to induce spontaneous in vitrodifferentiation and GPR17 protein expression. For terminaldifferentiation and quantification analyses of protein expression, after24-48 h the growth factor-free medium was supplemented with 0.20 ng/mLtriiodothyronine (T3) and 10 ng/mL ciliary neurotrophic factor togetherwith 1μM GPR17 antagonist/inverse agonists test compounds or vehicle foradditional 3 days. Following compound treatment, cells were washed twicewith ice-cold PBS and lysed in ice-cold lysis buffer (25 mM Tris, pH7.4, 150 mM NaCI, 1 mM EDTA, 1% Triton X-100, 1% IGEPAL) supplementedwith protease inhibitor mixture. Lysates were rotated 20 min at 4° C.and centrifuged at 15,000 x g at 4° C. for 10 min. Protein concentrationwas determined using the Pierce BCA Protein Assay according tomanufacturer's instructions. 7.5-15 pg of protein were separated by 10%SDS-polyacrylamide gel electrophoresis and transferred to nitrocellulosemembrane by electroblotting. After washing, membranes were blocked withRoti-Block for 1 h at room temperature and incubated overnight at 4 ° C.in Roti-Block with

MBP antibody (1:5000, LifeSpan BioSciences). Membranes were washed 3times with PBS containing 0.1% Tween and then incubated for 1 h at roomtemperature with a horseradish peroxidase-conjugated goat anti-mouse IgGantibody in Roti-Block. The immunoreactive proteins were visualized bychemiluminescence using Amersham Biosciences ECL Prime Western blottingdetection reagent and quantified by densitometry using Gelscan software.To normalize for equal loading and protein transfer, membranes werereprobed with an antibody against 13-actin (1:2500, BioLegend; secondaryantibody goat anti-rabbit IgG antibody HRP (ABIN)). Changes in MBPexpression level in the presence of test compounds were compared to MBPexpression in control conditions.

Description of MBP Fiber Plates/Oligodendrocyte Maturation/MyelinationAssay

OPCs were seeded at 16,000-22,000 cells per cm² in Mimetix Aligned96-well fiber plates (Electrospining company). After 2 days inproliferation medium and 2 days in growth factor-free Neurobasal mediumto induce spontaneous in vitro differentiation and GPR17 proteinexpression, vehicle or 1 μM antagonist/ inverse agonist test compoundswere added in terminal differentiation medium supplemented with 0.20ng/mL triiodothyronine and 10 ng/mL ciliary neurotrophic factor for 6days, changing the medium after 3 days. Then cells were fixed in 4%paraformaldehyde, followed by PBS washes, permeabilization in 0.1%TritonX-100 in PBS and blocking with 10% goat serum and 1% bovine serumalbumin in phosphate-buffered saline. MBP antibody was diluted inblocking buffer (1:2000) and incubated for 1 h at 37 ° C. Cells werewashed in PBS again and incubated 1 h with Cy2-conjugated secondaryantibodies against mouse IgG (Millipore, 1:500). After PBS washes, cellswere stained with 0.2 pg/mL DAPI, washed again and mounted with Mowiol.Fluorescent images were taken by using a Zeiss AxioObserver.Z1microscope with ApoTome Imaging System and a Plan-Apochromat 20×/0.8objective, with an eGFP filter (excitation 470/40 nm; emission 525/50nm) and DAPI filter (excitation 365 nm;

emission 445/50 nm). At least 15 random areas for control (terminaldifferentiation medium with 0.1% DMSO) and for test compounds wereimaged using the same settings processed with Zeiss ZEN2.3 software.Changes in number myelinated fibers was reported by group of fiberlengths (0 to 40 μm, 41 to 60 μm, 61 to 80, 81 to 100, 101 to 120and >120 μm)) in the absence or presence of GPR17 negative modulator.

Results of oligodendrocytes maturation/myelination assays

As depicted FIG. 1, when tested on primary rat OPCs inmaturation/myelination western blot assay, representative compounds ofthe Examples increased MBP expression, marker for matureoligodendrocytes.

The effect of Example I-116 on MBP expression was confirmed in the MBPfiber plates oligodendrocyte maturation/myelination assay. CompoundI-116 induced longer myelin sheaths as depicted on following graph. Thisdata is shown in FIG. 2.

B-111: Determination of plasma and brain exposure

Few Example compounds were tested to determine plasma and brainexposure.

Determination of Brain/Plasma ratio (brain Kp)

Male Sprague Dawley rats (n=2 per time point) were used to determine thebrain penetration of the compounds at 15, 45 and 120 min after 3 mg/kgof intraperitoneal administration.

At each time point, following anesthesia (inhalation of isoflurane) andblood collection (1 mL cardiac puncture into tubes containing K2EDTA)rats were exsanguinated and the brain perfused via the left ventricle(50mL of heparinized NaCI 0.9% (0.15U1/mL) flow 50mL/min).

Brain was collected and weighed. Plasma was obtained from blood samplesby centrifugation (3000g for 15 min at 4° C.). Brain and plasma sampleswere frozen until time of analysis.

At the time of analysis, brain samples were homogenized in plasma (1:4v:v) and together with plasma samples, following protein precipitation,were analyzed by HPLC/MS-MS analysis.

Results:

An Example compound (Example 1-1) is shown on FIG. 3. Compound I-1displayed brain concentrations paralleling plasma exposure approximately45 minutes after administration

B-IV: In vivo testing of an Example compound in the acute cuprizone micemodel

Compound 1-228 was tested in the well-established toxic demyelinationcuprizone mice model [see references 1-3 at the end of this Section]. Inthis model, feeding of cuprizone to young adult mice inducesoligodendrocytes cell death which is closely followed by microglia andastrocytes activation. Cuprizone feeding for 5 weeks leads to severe andhomogenous demyelination of the corpus callosum which can be reversedwhen the toxic treatment is interrupted (remyelination phase).

Animals and Cuprizone intoxication. C57BI/6J mice (Janvier, France) werebred and maintained in a pathogen-free environment with a maximum offive animals per cage. Animals have undergone routine cage maintenanceand microbiological monitoring according to the Federation of EuropeanLaboratory Animal Science Associations recommendations. Food (cuprizoneor standard chow) and water were available ad libitum. Demyelination wasinduced by feeding 8-week-old (+/−19-21g) male mice with a dietcontaining 0.25% cuprizone [bis(cyclohexanone)oxaldihydrazone;Sigma-Aldrich, Inc., USA] mixed into a ground standard rodent chow for 5weeks.

Tissue preparation and evaluation: For histological andimmunohistochemical studies, mice were anaesthetized with ketamine (100mg·kg−1; i.p.) and xylazine (10 mg·kg−1; i.p.), transcardially perfusedwith ice-cold PBS followed by transcardial perfusion with 3.7%paraformaldehyde solution (pH 7.4). Post-fixation was performed for 12hat 4° C. in the same fixative. Brains were then embedded in paraffin,and coronary sectioned into 5 μm sections at the level 265 (i.e.Region 1) and 285 (i.e. Region 2) according to the mouse brain atlas bySidman et al. (http://www.hms.harvard.edu/ research/brain/atlas.html).The myelin marker protein PLP has been visualized by means ofimmunohistochemistry. To this end, paraffin- embedded sections werede-waxed, rehydrated and washed in PBS. Unspecific bindings were omittedby incubating the slides for 1h with blocking solution at roomtemperature. The slides were incubated overnight with the primaryantibody diluted in blocking solution (Immunologic, Netherlands). On daytwo the slides were washed in BS, quenched in H202 and again washed inPBS. For the visualization of epitope-primary antibody complexes, wehave used EnVision® polymer secondary antibodies (Dako, Germany). Thissystem is based on a horseradish peroxidase-labelled polymer which isconjugated with secondary antibodies. The labeled polymer does notcontain avidin or biotin. Consequently, nonspecific staining resultingfrom endogenous avidin-biotin activity is eliminated or significantlyreduced. Additional negative controls have been performed by eitheromitting the primary antibody or incubating slides with respectiveconcentrations of IgG-subtypes. No specific staining has been observedin these control slides.

The intensity of the reaction product of anti-PLP immunohistochemistrywas measured semi- quantitatively using a Nikon Eclipse E-200 (50×)microscope coupled to a CCD camera and Image J-software. To this end,the region of interest was outlined (i.e. midline of the corpuscallosum, see highlighted in FIG. 4-1), and the picture converted to an8-bit greyscale image. Afterwards, a binary picture was created byapplying an auto threshold algorithm, and the relative area of thesignal was measured. For Region 1, the Yen algorithm was applied,whereas for Region 2, the Shanbhag/Moments algorithm was applied,respectively (see also FIG. 4-2).

Since the slides of all the groups were separately stained, a correctionfactor was applied to allow direct comparison of the results. Thiscorrection factor was determined based on visual inspection of theslides under the microscope. The used correction factors were of 0.33,0.75 and 7 respectively, depending on the regions analyzed. Twoconsecutive sections per region were analyzed. Values for each sectionwere used for statistics.

In order to evaluate demyelination in LFB-stained sections, magnitude ofmyelination was scored in the corpus callosum between 100 and 0. A scoreof 100 is equivalent to the myelin status of a mouse not treated withcuprizone, whereas zero is equivalent to a totally demyelinated corpuscallosum. Myelination values were obtained by inspection of twoconsecutive slides, one value per doublet was assessed.

Experimental design. Mice were fed with cuprizone for 5 weeks and wereallowed to recover from the intoxication for 11 days until tissuesamples collection (i.e. remyelination period). Vehicle or drugtreatment started after three full weeks of cuprizone feeding and werepursued until the end of the experiment (i.e. up to week 6.5). The drugwas daily administered orally (PO at a volume of administration of 10mL/kg. The experimental conditions were 1) vehicle 2) 6 mg/kg 3) 20mg/kg and, 60 mg/kg with a number of 10 animals per condition.

References: 1. Kipp et al, 2009 Acta Neuropathol 118: 723; 2. Kipp etal, 2011, Brain Behav Immun 25: 1554-1568; 3. Slowik et al, 2015, Br JPharmacol 172: 80-92.

Statistical analysis. The IHC analysis were done blind and to do so, thetreatment group assignment was only disclosed after the quality checkand the statistical analysis. Data were analysed using parametricstatistical analysis and Statistica software (StatSoft Inc., OK, USA).The dependent variable was the quantification of PLP measured in thecorpus callosum. As the analyses aimed at comparing four doses (0, 6, 20and 60 mg/kg), one-way ANOVA was applied. The between-mean differenceswas tested using Tukey's Honestly Significant Difference (HSD) test. Asnecessary, logarithmic transformations to normalise raw data prior tothe statistical analysis, was performed to more precisely meet theassumption of homogeneity of variances (Levene's test) and Gaussiandistribution. For the sake of clarity, however, means of the raw valuesare presented in the figures. Statistical significance was set atp<0.05. Data are expressed as mean ±SEM.

Results. The one-way ANOVA showed significant effect of the dose[F(3,70)=3.28, p<0.001] and Tukey post hoc test showed that the twogroups treated with the dose of 6 and 20 mg/kg had significant higherPLP levels in the comparison to the vehicle-treated group (p<0.01), seeFIG. 5.

Conclusion: Compound 1-228 accelerates the reappearance of themyelin-associated proteins after oral administration at 6 mg/kg and 20mg/kg in the cuprizone model. PLP being a marker of myelin, theseresults show that GPR17 inhibition by the compounds of the presentinvention either prevent demyelination or, more likely, promoteremyelination after cuprizone-induced demyelination. This is in linewith the recently published data obtained in the LPC induceddemyelination with GPR17 ko mice (Ou et al.,2016).

1.-30. (canceled)
 31. A method for treating a syndrome or disorderselected from a myelination disorder and a disorder or syndromeassociated with brain tissue damage, the method comprising administeringto a patient in need thereof a therapeutically effective amount of acompound having Formula I-2,

wherein X1 is N or C(R7), X2 is NH, S or 0, X3 is N or C(R12), R2 isselected from hydrogen, fluoro, chloro, bromo, iodo and methoxy, R4 isselected from hydrogen, methoxy and halogen, R5 is selected fromhydrogen, halogen, cyano, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkylcarbonyl,C₁₋₃alkoxycarbonyl, C₁₋₃alkylsulfinyl, and C₁₋₃alkylsulfonyl, whereineach alkyl or alkoxy may optionally be substituted one or more timeswith a substituent selected from halogen, C₁₋₃alkoxy, cyano, azido,hydroxyl, C₁₋₃alkylamino and di(C₁₋₃alkyl)amino, or R5 forms a ringtogether with R6, R6 is selected from hydrogen, fluoro, chloro, bromo,iodo, cyano, azido, nitro, unsubstituted or substituted C₁₋₃alkyl,unsubstituted or substituted C₁₋₃alkoxy, unsubstituted or substitutedC₂₋₃ alkenyl, unsubstituted or substituted C₂₋₃ alkynyl, unsubstitutedor substituted C₁₋₃alkylcarbonyl, unsubstituted or substitutedC₁₋₃alkoxycarbonyl, unsubstituted or substituted C₁₋₃alkylsulfinyl,unsubstituted or substituted C₁₋₃alkylsulfonyl, unsubstituted orsubstituted benzylsulfonyl, unsubstituted or substituted benzylsulfinyl,unsubstituted or substituted C₃₋₇ cycloalkyl, unsubstituted orsubstituted C₃₋₇ cycloalkyl(C₁₋₃)alkyl , unsubstituted or substitutedC₃₋₇ heterocycloalkyl, unsubstituted or substituted C₃₋₇heterocycloalkyl(C₁₋₃)alkyl, unsubstituted or substituted C₃₋₆cycloalkoxy, unsubstituted or substituted C₃₋₆ heterocycloalkoxy,unsubstituted or substituted C₁₋₅alkoxy(C₁₋₅)alkyl, unsubstituted orsubstituted C₁₋₃alkoxy(C₁₋₃)alkoxy, unsubstituted or substituted(C₃₋₆)cycloalkyl(C₁₋₃)alkoxy, unsubstituted or substituted(C₃₋₆)heterocycloalkyl)C₁₋₃)alkoxy, unsubstituted or substituted phenyl,unsubstituted or substituted phenyloxy, unsubstituted or substitutedthienyl, unsubstituted or substituted pyridyl, unsubstituted orsubstituted oxazole, unsubstituted or substituted thiazole,unsubstituted or substituted isoxazole, unsubstituted or substitutedphenyl(C₁₋₃)alkoxy, wherein each optional substitution in R6 is selectedfrom one or more of the group consisting of fluoro, chloro, bromo,unsubstituted or fluorinated methyl, unsubstituted or fluorinatedmethoxy, hydroxy and cyano, or (i) R6 forms together with R7 and thecarbon atoms to which R6 and R7 are attached, an unsubstituted orsubstituted phenyl, unsubstituted or substituted pyridyl, unsubstitutedor substituted cyclopentyl or unsubstituted or substituted cyclohexyl,wherein each substitution, if present, is selected from halogen,hydroxy, cyano, C₁₋₆ alkyl, C2-6 alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₃₋₇ cycloalkyl(C₁₋₃)alkyl, C₃₋₇ heterocycloalkyl(Ci-3)alkyl, C₁₋₆alkoxy, and C₁₋₆ alkoxy(C₁₋₃)alkyl,wherein each alkyl or alkoxy can beunsubstituted or substituted with one or more substituents selected fromhalogen and C₁₋₃alkoxy, or (ii) R6 forms together with R5 and the carbonatoms to which R6 and R5 are attached, a 1,3-dioxolane which may beunsubstituted or substituted with one or two substituents selected fromfluoro and methyl, R7 is selected from hydrogen, halogen, cyano,C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkylcarbonyl, C₁₋₃alkoxycarbonyl,C₁₋₃alkylsulfonyl, C₁₋₃alkylsulfinyl, C₅₋₆ heteroaryl, and C₅₋₆heteroaryl(C₁₋₃) alkoxy, wherein each alkyl or alkoxy moiety can beunsubstituted or substituted with one or more substituents selected fromthe group consisting of halogen, halo(C₁₋₆)alkoxy, and C₁₋₃alkoxy, andwherein each heteroaryl can be unsubstituted or substituted with one ormore substituents selected from the group consisting of halogen, methyl,hydroxy, and methoxy, or R7 forms a ring together with R6, R8 isselected from hydrogen, C₁₋₃alkyl, C₁₋₃alkoxy, cyano, and halogen,wherein each alkyl or alkoxy can be unsubstituted or substituted withone or more substituents selected from halogen, cyano and methoxy, or R8forms a ring system together with R9, as described herein, R9 isselected from hydrogen, C₁₋₃alkyl, C₂₋₃ alkoxy, fluoro, chloro, bromoand iodo, wherein each alkyl or alkoxy can be unsubstituted orsubstituted with one or more substituents selected from halogen andmethoxy, or R9 forms together with R8 or R10 and the ring to which theyare attached a bicyclic ring system selected from2,1,3-benzothiadiazole, 2,1,3-benzoselenadiazole, 2,1,3-benzoxadiazole,1,3-benzothiazole, 1,3-benzoxazole which may be unsubstituted or may bepartially hydrogenated and substituted with oxo,2-oxo-2,3-dihydro-1,3-benzoxazol, 1,3-benzodioxole which may beunsubstituted or substituted with one or two substituents selected fromfluoro and methyl, 2,2-difluoro-1,3-benzodioxol,2,3-dihydrobenzothiophene which may be unsubstituted or substituted withone or two oxo groups, 1,1-dioxido-2,3-dihydro-l-benzothiophen,1,3-dihydro-2-benzofuran which may be unsubstituted or substituted withone or two groups selected from oxo, fluoro and methyl,3-oxo-1,3-dihydro-2-benzofuran, 1-methyl-3-oxo-1,3-dihydro-2-benzofuran,dihydroisoindol which may be unsubstituted or substituted with one ormore substituents selected from oxo, fluoro and methyl, and3-oxo-2,3-dihydro-1H-isoindol, R10 is selected from hydrogen, fluoro,chloro, bromo, iodo, C₁₋₅ alkyl, C₁₋₅ alkoxy, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₃₋₄ cycloalkyl, C₃₋₄ heterocycloalkyl, cyano, cyanomethyl,cyanomethoxy, C₁₋₃alkylcarbonyl, C₁₋₃alkoxycarbonyl, azido,pentafluorosulfanyl, and nitro, wherein each alkyl, alkenyl, alkynyl oralkoxy can be unsubstituted or substituted with one or more substituentsselected from halogen, unsubstituted or fluorinated C₁₋₃alkoxy,unsubstituted or fluorinated C₁₋₃alkoxycarbonyl, unsubstituted orfluorinated C₁₋₃alkylcarbonyl, cyano, hydroxy, cyclopropyl and pyridyl,wherein the pyridyl may be optionally substituted with halogen,unsubstituted or fluorinated methyl and/or unsubstituted or fluorinatedmethoxy, and wherein any cycloalkyl or heterocycloalkyl can beunsubstituted or substituted with a group selected from halogen, cyano,hydroxy(C₁₋₂)alkyl, C₁₋₂alkoxy and C₁₋₂alkoxycarbonyl, or R10 forms aring system together with R9, R11 is selected from hydrogen, C₁₋₃alkyl,C₁₋₃alkoxy, fluoro, chloro, bromo, iodo, cyano, C₁₋₃alkylcarbonyl, andC₁₋₃alkoxycarbonyl, wherein each alkyl and alkoxy can be unsubstitutedor substituted with one or more substituents selected from fluoro,chloro, bromo, iodo and C₁₋₃alkoxy, R12, if present, is selected fromhydrogen, C₁₋₃alkyl, C₁₋₃alkoxy, fluoro, chloro, bromo, and iodo,wherein each alkyl and alkoxy can be unsubstituted or substituted withone or more substituents selected from fluoro, chloro, bromo, iodo andC₁₋₃alkoxy, and pharmaceutically acceptable salts, solvates, isotopesand co-crystals thereof.
 32. The method according to claim 31, whereinX1 is N or C(R7), X2 is NH, S or 0, X3 is N or C(R12), R2 and R4 areboth hydrogen, R5 is selected from hydrogen, fluoro, chloro and bromo,R6 is selected from fluoro, chloro, bromo, iodo, cyano, azido, nitro,methyl, ethyl, propyl, isopropyl, trifluoromethyl, ethenyl, ethynyl,propargyl, methylsulfinyl, methylsulfonyl, cyclopropyl, cyclopropyloxy,cyclopropylmethyl, methoxy, ethoxy, propoxy, methoxyethoxy,ethoxymethoxy, cyclopropylmethoxy, oxetanyl, oxetanylmethoxy,tetrahydrofuranyl, tetrahydrofuranylmethoxy, phenyl, benzyloxy,phenyloxy, benzylsulfinyl, thienyl, pyridyl, oxazole, thiazole, andisoxazole, wherein each phenyl, thienyl, pyridyl, oxazol, thiazole andisoxazol can be optionally substituted one or more times with asubstitution selected from halogen, methoxy, and methyl, and whereineach alkyl, alkenyl, alkynyl, and alkoxy group can be substituted one ormore times with fluoro, methoxy, fluoromethoxy, and hydroxy, or R6 formstogether with R7 and the carbon atoms to which R6 and R7 are attached, aring selected from phenyl, pyridyl, cyclohexyl, and cyclopentyl, each ofwhich can be unsubstituted or further substituted with one or moreresidues selected from halogen, hydroxy, unsubstituted or fluorinatedmethyl, and unsubstituted or fluorinated methoxy, R7 is selected fromhydrogen, fluoro, chloro, bromo, iodo, cyano, methylsulfinyl,methylsulfonyl, methoxy, fluoromethoxy, fluoroethoxy, methyl,fluoromethyl, and fluoroethyl, or R7 forms a ring together with R6, R8is selected from hydrogen, fluoro, chloro, bromo, iodo, methoxy,fluoromethoxy, cyano, methyl, and fluoromethyl, or R8 forms a ringsystem together with R9, R9 is selected from hydrogen, fluoro andchloro, or R9 forms together with R8 or R10 and the ring to which theyare attached a bicyclic ring system selected from 2,1,3-benzothiadiazole, 2,1,3 -benzoxadiazole, 2-oxo-2,3 -dihydro -1,3-benzoxazole and 1,3-benzodioxole, which is optionally substituted withtwo fluoros, or R9 forms together with R10 and the ring to which theyare attached a bicyclic ring system selected from3-oxo-2,3-dihydro-1H-isoindol, 2,3-dihydro-l-benzothiophene, which issubstituted with one or two oxo, and optionally methylated3-oxo-1,3-dihydro-2-benzofuran, R10 is selected from hydrogen, fluoro,chloro, bromo, iodo, methyl, ethyl, n-propyl, isopropyl, ethenyl,n-propenyl, isopropenyl, ethynyl, propargyl, fluoro(C₁₋₃)alkyl, methoxy,ethoxy, propoxy, fluoro(C₁₋₃)alkoxy, C₁₋₃alkoxy(C₁₋₃)alkyl,C₁₋₃alkoxy(C₁₋₃)alkoxy, C₁₋₃alkoxy(C₂₋₃)alkenyl,C₁₋₃alkoxy(C₂₋₃)alkynyl, C₁₋₃alkoxycarbonyl(C₁₋₃)alkyl,C₁₋₃alkylcarbonyl(C₁₋₃)alkyl, C₁₋₃ alkylcarbonyl(C₁₋₃)alkyloxy, cyano,acetyl, azido, nitro, pentafluorosulfanyl, cyclopropyl, cyclopropyloxy,cyclopropylmethoxy, and (C₁₋₃)alkoxycarbonyl, wherein each alkyl,alkenyl, alkynyl and alkoxy group in R10 can be unsubstituted orsubstituted with one or more residues selected from fluoro, cyano and/orhydroxy, and wherein the cyclopropyl is optionally substituted with oneor more residues selected from cyano, optionally fluorinated C₁₋₂ alkoxyand optionally fluorinated C₁₋₂alkoxycarbonyl, or R10 forms a ringsystem together with R9, R11 is selected from hydrogen, fluoro, chloro,bromo, cyano, methyl, fluoromethyl, methoxy and fluoromethoxy, R12, ifpresent, is selected from hydrogen, fluoro, chloro and bromo, wherein atleast two of R8, R10 and R11 are different from hydrogen, andpharmaceutically acceptable salts, solvates, isotopes and co-crystalsthereof.
 33. The method according to claim 31, wherein X1 is N or C(R7),X2 is NH, S or 0, X3 is N or C(R12), R2 and R4 are both selected fromhydrogen and fluoro, R5 is selected from hydrogen and halogen, R6 isselected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido,nitro, unsubstituted or fluorinated C₁₋₃alkyl, unsubstituted orfluorinated C₁₋₃alkoxy, methylsulfinyl, methylsulfonyl, cyclopropyl,cyclopropylmethyl, cyclopropylmethoxy, benzyloxy, benzylsulfinyl,thienyl and pyridyl, R7 is selected from hydrogen, fluoro, chloro,bromo, cyano, methyl, methoxy, fluoromethyl, fluoromethoxy,methylsulfinyl and methylsulfonyl, R8 is selected from hydrogen, fluoro,chloro, cyano, methoxy and fluoromethoxy, R9 is hydrogen or fluoro, R10is selected from fluoro, chloro, bromo, iodo, azido, cyano, oxetanyl,cyano(C₁₋₂)alkyl, cyano(C₁₋₂)alkoxy, cyclopropyl(C₁₋₂)alkyl,cyclobutyl(C₁₋₂)alkyl, cyclopropyl(C₁₋₂)alkoxy, optionally fluorinatedC₁₋₂alkoxycyclopropyl, optionally fluorinatedC₁₋₂alkoxycarbonylcyclopropyl, unsubstituted or fluorinated C₁₋₃alkyl,unsubstituted or fluorinated C₁₋₃ alkoxy, unsubstituted or fluorinatedC₂₋₃ alkenyl, unsubstituted or fluorinated C₂₋₃ alkynyl, unsubstitutedor fluorinated C₁₋₃alkoxy(C₁₋₃)alkyl, unsubstituted or fluorinatedC₁₋₃alkoxy(C₁₋₃)alkoxy, unsubstituted or fluorinatedC₁₋₃alkoxy(C₂₋₃)alkenyl, and pentafluorosulfanyl, R11 is selected fromhydrogen, fluoro, chloro, methoxy, fluoromethoxy and fluoromethyl, R12,if present, is hydrogen or fluoro, wherein at least one of R8 and R11 isdifferent from hydrogen, and pharmaceutically acceptable salts,solvates, isotopes and co-crystals thereof.
 34. The method according toclaim 31, wherein X1 is N or C(R7), X2 is NH, X3 is N or CR12, R2 and R4are both hydrogen, R5 is selected from hydrogen, fluoro, chloro andbromo, R6 is selected from fluoro, bromo, chloro, azido, cyano, methyl,fluoromethyl, ethyl, fluoroethyl, isopropyl, cyclopropyl,cyclopropylmethyl, cyclopropylmethoxy, methoxy, ethoxy, fluoromethoxy,fluoroethoxy, methylsulfinyl, methylsulfonyl, benzyloxy and thienyl, R7is selected from hydrogen, methoxy, fluoro, chloro, bromo, cyano,fluoromethoxy, fluoroethoxy, and mono-, di- and trifluoromethyl, R8 isselected from hydrogen, fluoro, chloro, and methoxy, R9 is hydrogen orfluoro, R10 is selected from fluoro, chloro, bromo, cyano, cyanomethyl,cyanoethyl, cyanomethoxy, azido, methyl, ethyl, propyl, ethenyl,propenyl, ethynyl, propargyl, mono-, di-, and trifluoromethyl,cyclopropylmethoxy, cyclopropylethoxy, methoxycyclopropyl,ethoxycyclopropyl, methoxycarbonylcyclopropyl,ethoxycarbonylcyclopropyl, mono-, di- and trifluoromethoxy, mono-, di-,and trifluoroethoxy, ethoxymethyl, methoxyethyl, ethoxyethyl,methoxypropyl, fluoroethoxymethyl, fluoromethoxyethyl,fluoroethoxyethyl, fluoromethoxypropyl, ethoxymethoxy, methoxyethoxy,methoxypropoxy, fluoroethoxymethoxy, fluoromethoxyethoxy,fluoromethoxypropoxy, methoxyethenyl, methoxypropenyl,fluoromethoxyethenyl, ethynyl, propargyl, and pentafluorosulfanyl, R11is selected from hydrogen, fluoro, chloro, fluoromethyl, methoxy, andfluoromethoxy, R12, if present, is hydrogen or fluoro, wherein at leastone of R8 and R11 is different from hydrogen, and pharmaceuticallyacceptable salts, solvates, isotopes and co-crystals thereof.
 35. Themethod according to claim 31, wherein the compound of Formula I-2corresponds in structure to Formula II

or corresponds in structure to Formula III

wherein X3 is N or C(R12), R4 is hydrogen, R5 is selected from hydrogen,fluoro, chloro and bromo, R6 is selected from fluoro, chloro, bromo,iodo, cyano, azido, nitro, methyl, ethyl, n-propyl, isopropyl,trifluoromethyl, methylsulfinyl, methylsulfonyl, cyclopropyl,cyclopropylmethyl, methoxy, ethoxy, methoxymethoxy, methoxyethoxy,ethoxymethoxy, cyclopropylmethoxy, phenyl, benzyloxy, phenyloxy,benzylsulfinyl, benzylsulfonyl, thienyl, pyridyl, oxazole, thiazole, andisoxazole, wherein each alkyl and alkoxy group in R6 can be substitutedwith one or more residues selected from fluoro, cyano, and hydroxy andwherein each phenyl, thienyl, pyridyl, oxazol, thiazole and isoxazol canbe optionally substituted one or more times, or, in the compounds offormula II, R6 together with R7 and the carbon atoms to which R6 and R7are attached may form a ring selected from phenyl, pyridyl, cycloxhexyland cyclopentyl, each of which can be unsubstituted or substituted oneor more times with a group selected from methyl, fluorinated methyl,methoxy, fluorinated methoxy, hydroxy, chloro and fluoro, R7, in thecompounds of Formula II, is selected from hydrogen, fluoro, chloro,bromo, iodo, cyano, methoxy, ethoxy, methylsulfinyl, methylsulfonyl,methyl, ethyl, fluoromethyl, fluoroethyl, and fluoro(C₁₋₂)alkoxy, or R7forms a ring together with R6, R8 is selected from hydrogen, fluoro,chloro, bromo, iodo, methoxy, fluoromethyl and fluoromethoxy, or R8forms a ring system together with R9, R9 is selected from hydrogen,methyl, fluoro and chloro, or R9 forms together with R8 or R10 and thering to which they are attached a bicyclic ring system selected from 2,1,3 -benzothiadiazole, 2, 1,3 -benzoxadiazole, 2-oxo-2,3-dihydro- 1,3-benzoxazole and 1,3-benzodioxole, which is optionally substituted withtwo fluoros, or R9 forms together with R10 and the ring to which theyare attached a bicyclic ring system selected from 3 -oxo-2,3 -dihydro- 1H-is oindol, 1 , 1 -dioxo-2,3 -dihydro- 1 -benzothiophene and 3-oxo-1,3-dihydro-2-benzofuran which can be optionally methylated in 1position, R10 is selected from hydrogen, fluoro, chloro, bromo, iodo,unsubstituted or fluorinated C₁₋₃alkenyl including ethenyl and propenyl,unsubstituted or fluorinated C₁₋₃alkynyl including ethynyl andpropargyl, unsubstituted or fluorinated and/or hydroxylated C₁₋₃akylincluding methyl, ethyl, isopropyl and trifluoromethyl, unsubstituted orfluorinated and/or hydroxylated C₁₋₃alkoxy including methoxy andfluoro(C₁₋₂)alkoxy, cyano, cyanomethyl, cyanomethoxy, cyclopropyl,cyclopropylmethoxy, cyclopropylethoxy, acetyl, azido, nitro,pentafluorosulfanyl, unsubstituted or fluorinated and/or hydroxylatedC₁₋₃alkoxy(C₁₋₃)alkyl, unsubstituted or fluorinated and/or hydroxylatedC₁₋₃alkoxy(C₁₋₃)alkoxy, unsubstituted or fluorinated and/or hydroxylatedC₁₋₃alkoxy(C₂₋₃)alkenyl, unsubstituted or fluorinated and/orhydroxylated C₁₋₃alkoxy(C₂₋₃)alkynyl, unsubstituted or fluorinatedand/or hydroxylated C₁₋₃ alkoxycarbonyl(C₁₋₃)alkyl, and unsubstituted orfluorinated and/or hydroxylated C₁₋₃alkoxycarbonyl(C₁₋₃)alkenyl, whereineach cyclopropyl group in R10 may be unsubstituted or furthersubstituted with one or more substituents selected from fluoro, chloro,cyano, optionally fluorinated C₁₋₂alkoxy and optionally fluorinatedC₁₋₂alkoxycarbonyl, or R10 forms a ring system together with R9, R11 isselected from hydrogen, fluoro, chloro, bromo, unsubstituted orfluorinated methyl, and unsubstituted or fluorinated methoxy, R12, ifpresent, is selected from hydrogen, fluoro, chloro, or bromo, wherein atleast one of R8, R10 and R11, is different from hydrogen andunsubstituted alkyl, and pharmaceutically acceptable salts, solvates,isotopes and co-crystals thereof.
 36. The method according to claim 35,wherein R4 and R5 are both hydrogen, R6 is selected from fluoro, chloro,bromo, methoxy, fluoromethoxy and fluoromethyl, R7, in the compounds ofFormula II, is selected from hydrogen, methoxy, fluoro, chloro, bromo,fluoromethyl, fluoromethoxy, fluoroethoxy, methylsulfinyl andmethylsulfonyl, X3 is N or CR12, R8 is fluoro or methoxy, R9 ishydrogen, R10 is selected from fluoro, chloro, bromo, cyano,cyanomethyl, cyanoethyl, cyanomethoxy, unsubstituted or fluorinatedC₁₋₃alkyl, unsubstituted or fluorinated C₁₋₃alkoxy, unsubstituted orfluorinated C₁₋₂alkoxy(C₁₋₃)alkyl, unsubstituted or fluorinatedC₁₋₂alkoxy(C₂₋₃)alkenyl, unsubstituted or fluorinatedC₁₋₂alkoxy(C₁₋₃)alkoxy, pentafluorosulfanyl and cycloalkyl, which issubstituted with a substituent selected from C₁₋₂alkoxy,fluoro(C₁₋₂)alkoxy, C₁₋₂alkoxycarbonyl and fluoro(C₁₋₂)alkoxycarbonyl,R11 is selected from hydrogen, methoxy, fluoromethoxy, fluoromethyl, andfluoro, R12, if present, is hydrogen or fluoro, and pharmaceuticallyacceptable salts, solvates, isotopes and co-crystals thereof.
 37. Themethod according to claim 35, wherein R4 is hydrogen, R5 is selectedfrom hydrogen, fluoro, chloro and bromo, R6 is selected from fluoro,chloro, bromo, iodo, cyano, nitro, methyl, ethyl, isopropyl,fluoromethyl, fluoroethyl, methoxy, fluoromethoxy, fluoroethoxy, cyano,methylsulfinyl, methylsulfonyl, cyclopropyl, phenyl, benzyloxy,2-thienyl and 3-thienyl, R7 is selected from hydrogen, fluoro, chloro,bromo, cyano, fluoro(C₁₋₂)alkyl, and fluoro(C₁₋₃)alkoxy, X3 is C(R12),R8 and R11 are independently selected from hydrogen, fluoro, chloro,cyano, fluoromethyl, methoxy and fluoromethoxy, R9 is hydrogen, R10 isselected from fluoro, chloro, bromo, iodo, azido, unsubstituted orfluorinated C₁₋₃alkyl, unsubstituted or fluorinated C₁₋₃alkyloxy,unsubstituted or fluorinated C₁₋₃alkoxy(C₁₋₃)alkyl, unsubstituted orfluorinated C₁₋₃alkoxy(C₁₋₃)alkoxy, unsubstituted or fluorinatedC₁₋₃alkoxy(C₂₋₃)alkenyl, pentafluorosulfanyl, ethynyl, propynyl, cyano,cyanomethoxy, and cyanomethyl, and R12 is hydrogen and fluoro, whereinat least one of R8 and R11 is fluoro.
 38. The method according to claim35 and having Formula III, wherein R4 and R5 are both hydrogen, R6 isselected from hydrogen, fluoro, chloro, bromo, fluoromethyl, methoxy,fluoromethoxy, and cyclopropyl, X3 is C(R12) or N, R8 is selected fromhydrogen, methoxy, and halogen, R9 is hydrogen, R10 is selected fromfluoro, bromo, chloro, iodo, methyl, fluoro(C₁₋₃)alkyl, unsubstituted orfluorinated methoxy(C₁₋₃)alkyl, unsubstituted or fluorinatedC₁₋₃alkyloxy, unsubstituted or fluorinated methoxy(C₁₋₃)alkyloxy,unsubstituted or fluorinated C₂₋₃alkenyl, unsubstituted or fluorinatedmethoxy(C₂₋₃)alkenyl, ethynyl, propargyl, unsubstituted or fluorinatedmethoxy(C₂₋₃)alkynyl, azido, pentafluorosulfanyl, cyanomethyl,cyanoethyl, and cyano, R11 is hydrogen, fluoro, chloro, or methoxy, R12,if present, is hydrogen or fluoro, and pharmaceutically acceptablesalts, solvates, isotopes and co-crystals thereof.
 39. The methodaccording to claim 35 and having formula III, wherein wherein R4 and R5are both hydrogen, R6 is selected from chloro, bromo, methoxy, mono-,di-, and trifluoromethyl, X3 is C(R12) or N, R8 is selected fromhydrogen, fluoro, chloro, methoxy and fluoromethoxy, R9 is hydrogen, R10is selected from fluoro, chloro, bromo, cyano, cyanomethyl, cyanoethyl,cyanomethoxy, mono-, di-, and trifluoromethyl, mono-, di-, andtrifluoromethoxy, mono-, di-, and trifluoroethoxy, unsubstituted orfluorinated C₁₋₂alkoxy(C₁₋₃)alkoxy, unsubstituted or fluorinatedC₁₋₂alkoxy(C₁₋₃)alkyl, unsubstituted or fluorinated C₂₋₃alkenyl,unsubstituted or fluorinated C₁₋₂alkoxy(C₂₋₃)alkenyl, and C₂₋₃alkynyl,R11 is selected from hydrogen, methoxy, fluoro and chloro and R12, ifpresent, is hydrogen or fluoro.
 40. The method according to claim 31,wherein X3 is N, thus having the structure of Formula VI:

wherein Xl, X2, R2, R4, R5, R6, R8, R9, R10 and R11 have the meaning asdescribed in claim
 31. 41. The method according to claim 40, wherein X1is C-R7 or N, X2 is NH, R2 and R4 are both hydrogen, R5 is selected fromhydrogen, fluoro, chloro and bromo, R6 is selected from fluoro, chloro,bromo, cyano, azido, nitro, C₁₋₃alkyl, C₁₋₃alkyloxy, cyclopropyl,cyclopropyloxy, oxetanyl, tetrahydrofuranyl, methylsulfonyl,methylsulfinyl, thienyl, pyridyl, and benzyloxy, wherein each alkyl oralkoxy group in R6 can be unsubstituted or substituted with one or moregroups selected from fluoro, chloro, bromo, unsubstituted or fluorinatedC₁₋₂alkyloxy and cyclopropyl and wherein each cyclopropyl, thienyl,pyridyl and phenyl group in R6 can be substituted with one or moregroups selected from halogen, methoxy, fluoromethoxy, methyl,fluoromethyl and cyano, or R6 forms together with R7 and the carbonatoms to which R6 and R7 are attached, an unsubstituted or substitutedphenyl, an unsubstituted or substituted pyridyl, an unsubstituted orsubstituted cyclopentyl or an unsubstituted or substituted cyclohexyl,wherein each substitution in R7, if present, is selected from hydroxy,halogen, methyl and methoxy, wherein each methyl or methoxy can beunsubstituted or fluorinated, R7, if present, is selected from hydrogen,halogen, cyano, C₁₋₃alkyl, C₁₋₃alkoxy, methylsulfinyl andmethylsulfonyl, wherein each alkyl or alkoxy group in R7 can beunsubstituted or substituted with one or more groups selected fromfluoro, chloro, cyano, and unsubstituted or fluorinated C₁₋₂alkyloxy, orR7 forms a ring together with R6 as described herein, R8 is selectedfrom fluoro, chloro, unsubstituted or fluorinated methyl, andunsubstituted or fluorinated methoxy, R9 is selected from hydrogen,fluoro, methyl, fluoromethyl, methoxy, and fluoromethoxy, R10 isselected from halogen, C₁₋₃alkyl, C₁₋₃alkyloxy, C₂₋₃alkenyl,C₂₋₃alkynyl, C₁₋₃ alkylcarbonyl, C₃₋₄cycloalkyl, C₃₋₄cycloalkyloxy,C₃₋₄heterocycloalkyl, C₃₋₄heterocycloalkyloxy and cyano, wherein eachalkyl, alkenyl, alkynyl or alkoxy can be unsubstituted or substitutedwith one or more substituents selected from fluoro, chloro, bromo,fluorinated or unsubstituted C₁₋₃alkyloxy, fluorinated or unsubstitutedC₁₋₃alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₃₋₅cycloalkyl,C₃₋₅cycloalkyloxy, C₃₋₅heterocycloalkyl, C₃₋₅heterocycloalkyloxy,hydroxy and cyano, wherein any C₃₋₅cycloalkyl and hetero(C₃₋₅)cycloalkylmay be unsubstituted or substituted with one or more residues selectedfrom halogen, hydroxy, hydroxymethyl, cyano, fluorinated orunsubstituted methyl, fluorinated or unsubstituted methoxy andfluorinated or unsubstituted C₁₋₃(C₁₋₃)alkyloxy, R11 is selected fromhydrogen, fluoro, chloro, bromo, unsubstituted or fluorinated C₁₋₃alkyl,and unsubstituted or fluorinated C₁₋₃alkyloxy, and pharmaceuticallyacceptable salts, solvates, isotopes and co-crystals thereof.
 42. Themethod according to claim 40 and having one of the following formulaeVIa, VIb, VIc or VId:

wherein R2 and R4 are both hydrogen, R5 is selected from hydrogen,fluoro, chloro and bromo, R6 is selected from fluoro, chloro, bromo,azido, cyano, benzyloxy, methylsulfonyl, methylsulfinyl, C₁₋₃alkyl,C₁₋₃alkyloxy, cyclopropyl, cyclopropyloxy and cyclopropylmethoxy,wherein each alkyl, alkoxy and cyclopropyl group in R6 can beunsubstituted or substituted with one or more groups selected fromfluoro, chloro, bromo and unsubstituted or fluorinated C₁₋₂alkyloxy,wherein in the compounds of formula VIa, VIb or VIc, R6 may also formtogether with R7 and the carbon atoms to which R6 and R7 are attached,an unsubstituted or substituted phenyl, an unsubstituted or substitutedpyridyl, an unsubstituted or substituted cyclopentyl or an unsubstitutedor substituted cyclohexyl, wherein each substitution in R7, if present,is selected from hydroxy, halogen, cyano, methyl and methoxy, whereineach methyl or methoxy can be unsubstituted or fluorinated and/orhydroxylated, R7, if present, is selected from hydrogen, halogen, cyano,C₁₋₃alkyl, C₁₋₃alkyloxy, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyloxy,methylsulfinyl and methylsulfonyl, wherein alkyl, alkoxy or cycloalkylgroup in R7 can be unsubstituted or substituted with one or more groupsselected from fluoro, chloro, cyano and unsubstituted or fluorinatedC₁₋₂alkyloxy, or R7 forms a ring together with R6 as described herein,R8 is selected from hydrogen, fluoro, chloro, unsubstituted orfluorinated methoxy and unsubstituted or fluorinated methyl, R9 isselected from hydrogen, fluoro, methyl and methoxy, R10 is selected fromhydrogen, halogen, cyano, C₁₋₃alkyl, C₂₋₃alkenyl, C₂₋₃akynyl,C₁₋₃alkyloxy, C₃₋₄cycloalkyl, C₃₋₄cycloalkyloxy, C₃₋₄heterocycloalkyl,and C₃₋₄heterocycloalkyloxy, wherein each alkyl, alkenyl, alkynyl andalkyloxy group in R10 can be unsubstituted or substituted with one ormore groups selected from fluoro, chloro, bromo, fluorinated orunsubstituted C₁₋₃alkyloxy, fluorinated or unsubstitutedC₁₋₃akylcarbonyl, fluorinated or unsubstituted C₁₋₃alkoxycarbonyl,C₃₋₄cycloalkyl, C₃₋₄cycloalkyloxy, C₃₋₄heterocycloalkyl,C₃₋₄heterocycloalkyloxy, hydroxy, and cyano, and wherein each cycloalkyland heterocycloalkyl group in R10 can be substituted with a residueselected from fluoro, chloro, bromo, hydroxy, hydroxymethyl, fluorinatedor unsubstituted C₁₋₃alkyl, fluorinated or unsubstituted C₁₋₃alkyloxy,fluorinated or unsubstituted C₁₋₂alkyloxyC₁₋₂alkyloxy and fluorinated orunsubstituted C₁₋₃alkoxycarbonyl, R11 is selected from hydrogen, fluoro,chloro, bromo, unsubstituted or fluorinated methyl, and unsubstituted orfluorinated methoxy, and pharmaceutically acceptable salts, solvates,isotopes and co-crystals thereof.
 43. The method according to claim 42,and having one of Formula VIa, VIb, VIc and VId, wherein R2, R4, R5 andR9 are all hydrogen, R6 is selected from halogen, cyano, C₁₋₃alkoxy,C₁₋₃alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkyloxy, C₃₋₆heterocycloalkyl, andC₃₋₆heterocycloalkyloxy, each of which can be optionally substitutedwith a residue selected from fluoro and unsubstituted or fluorinatedC₁₋₃alkoxy, R7, if present, is selected from hydrogen, halogen, cyano,C₁₋₃alkoxy, C₁₋₃alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkyloxy,C₃₋₆heterocycloalkyl, and C₃₋₆heterocycloalkyloxy, each of which can beoptionally substituted with a residue selected from fluoro andunsubstituted or fluorinated C₁₋₃alkoxy, R8 is selected from fluoro,methoxy and fluoromethoxy, R10 is selected from halogen, C₁₋₄alkoxy,C₁₋₄alkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkyloxy,C₃₋₆heterocycloalkyl, and C₃₋₆heterocycloalkyloxy, each of which can beoptionally substituted with a residue selected from fluoro, cyano andunsubstituted or fluorinated C1-3alkoxy, and R11 is selected fromhydrogen, fluoro, methoxy and fluoromethoxy, and pharmaceuticallyacceptable salts, solvates, isotopes and co-crystals thereof.
 44. Themethod according to claim 42, and having one of Formula VIa, VIb, VIcand VId, wherein R2, R4 and R5 are all hydrogen, R6 is selected fromfluoro, chloro, bromo, methylsulfinyl, methyl, fluoromethyl, methoxy andfluoromethoxy, R7, if present, is selected from hydrogen, fluoro,chloro, bromo, unsubstituted or fluorinated C₁₋₂alkyl, unsubstituted orfluorinated C₁₋₂alkoxy, methylsulfinyl, and methylsulfonyl, R8 isselected from hydrogen, fluoro, chloro, methoxy and fluoromethoxy, R9 isselected from hydrogen, methoxy and fluoro, R10 is selected from isselected from halogen, cyano, cyanomethyl, cyanoethyl, unsubstituted orfluorinated C₁₋₃alkyl, unsubstituted or fluorinated C₁₋₃alkoxy,unsubstituted or fluorinated C₁₋₂alkoxy(C₁₋₃)alkyl, unsubstituted orfluorinated C₁₋₂alkoxy(C₁₋₃)alkoxy, unsubstituted or fluorinatedC₁₋₂alkoxy(C₂₋₃)alkenyl, unsubstituted or fluorinatedC₁₋₂alkoxycarbonylcyclopropyl and unsubstituted or fluorinatedC₁₋₃alkoxycyclopropyl, R11 is selected from hydrogen, fluoro, chloro,fluoromethyl, methoxy, and fluoromethoxy, wherein at least one of R8 andR10 is different from hydrogen, and pharmaceutically acceptable salts,solvates, isotopes and co-crystals thereof.
 45. The method according toclaim 31, wherein R6 and R7 together with the carbon atoms to which R6and R7 are attached, form a cycle such that the compound has a structureof one the following Formulae IIa - IIc:

wherein n is any number from 0 to 4, m is 0 or 1, p is any number from 0to 3, any Y is a substitution independently selected from fluoro,chloro, cyano, hydroxy, methyl, fluoromethyl, methoxy and fluoromethoxy,R4, R5, X3, R8, R9, R10, R11 and R12 (if X3 is C-R12) are as describedin the compounds of Formula I, and II herein, and pharmaceuticallyacceptable salts, solvates, isotopes and co-crystals thereof.
 46. Themethod according to claim 45, wherein m is 0 or 1, n is 0, 1 or 2, p is0, 1 or 2, any Y is selected from hydrogen, halogen, hydroxy,unsubstituted or fluorinated methyl and unsubstituted or fluorinatedmethoxy, R4 and R5 are both hydrogen, R8 is fluoro or methoxy, X3 is Nor C(R12), R9 is hydrogen, R10 is selected from halogen, ethynyl,propynyl, cyano, cyanomethyl, cyanoethyl, cyanomethoxy, unsubstituted orfluorinated (C₁₋₃)alkyl, unsubstituted or fluorinated (C₂₋₃)alkenyl,unsubstituted or fluorinated (C₂₋₃)alkynyl, unsubstituted or fluorinatedC₁₋₃alkyloxy, unsubstituted or fluorinated methoxy(C₁₋₃)alkyl,unsubstituted or fluorinated methoxy(C₁₋₃)alkyloxy, unsubstituted orfluorinated methoxy(C₂₋₃)alkenyl, unsubstituted or fluorinatedmethoxy(C₂₋₃)alkynyl and pentafluorosulfanyl, R11 is selected fromhydrogen, fluoro, and methoxy, and R12, if present, is hydrogen orfluoro, and pharmaceutically acceptable salts, solvates, isotopes andco-crystals thereof.
 47. The method according to claim 31, wherein R9forms a ring with R8 or R10 and the carbon atoms to which they areattached such that the compound has one of the following FormulaeIId-IIg

wherein in the compounds (a) of Formula II(d), Q1 is S or O, (b) ofFormula II(e), R13 and R14 are selected from the group of hydrogen,methyl and fluoro, (c) of Formula II(f), Q2 is S or O, and (d) ofFormula II(g), R16 is selected from hydrogen, fluoro, hydroxy, methyl,fluoromethyl, methoxy and fluoromethoxy, and pharmaceutically acceptablesalts, solvates, isotopes and co-crystals thereof.
 48. A compoundaccording to claim 47, wherein (a) in Formula II(d), Q1 is S or O, (b)in Formula II(e), R13 and R14 are both selected from hydrogen andfluoro, (c) in Formula II(f), Q2 is S or O (d) in Formula II(g), R16 isselected from hydrogen and methyl, and R4 is hydrogen, R5 is selectedfrom hydrogen, fluoro, chloro and bromo, R6 is selected from fluoro,chloro, bromo, methyl, methoxy, methylsulfonyl, methylsulfinyl,fluoromethyl, fluoromethoxy, cyano, and benzyloxy, R7 is selected fromhydrogen, fluoro, chloro, bromo, methoxy, cyano, methyl, andfluoromethyl, R8, if present, is selected from hydrogen and halogen,R10, if present, is selected from hydrogen, fluoro, chloro, bromo,fluoromethyl, fluoromethoxy and cyano, R11 is selected from hydrogen andfluoro, R12 is selected from hydrogen, halogen, methoxy andfluoromethyl, and pharmaceutically acceptable salts, solvates, isotopesand co-crystals thereof.
 49. The method according to claim 31, having astructure of one of the following Formulae III(a) to III(c)

wherein in a compound (a) of Formula III(a), Q1 is S or O, (b) ofFormula III(b), R13 and R14 are selected from the group of hydrogen,methyl and fluoro, and (c) in Formula III(c), Q2 is S or O,
 50. Themethod according to claim 49, wherein R4 and R5 are both hydrogen, R6 isselected from fluoro, chloro, bromo, trifluoromethyl, and phenyl, R8, ifpresent, is hydrogen or fluoro, R10, if present, is selected fromhydrogen and halogen, R11 is selected from hydrogen, halogen,trifluoromethyl and cyano, R12 is selected from hydrogen, halogen andtrifluoromethyl, and pharmaceutically acceptable salts, solvates,isotopes and co-crystals thereof.
 51. The method according to claim 31,wherein the compound is selected from the group consisting of:N-(4-bromo-2,5-difluorophenyl)-6-chloro-1H-indole-3-sulfonamie,6-bromo-N-(4-cyano-2,5-difluorophenyl)-1H-indole-3-sulfonamide,6-chloro-N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamide,N-(4-chloro-2,5-difluorophenyl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide,N-(4-bromo-2,5-difluorophenyl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide,6-chloro-N-(4-chloro-2,5-difluorophenyl)-1H-indole-3-sulfonamide,6-chloro-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-1H-indole-3-sulfonamide,N-[4-(cyanomethyl)-2,5-difluorophenyl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide,6-bromo-N-[3,6-difluoro-5-(3-methoxypropyl)pyridin-2-yl]-1H-indole-3-sulfonamide,N-(5-bromo-3,6-difluoropyridin-2-yl)-6-chloro-1H-indole-3-sulfonamide,N-(4-bromo-2,5-difluorophenyl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-7-fluoro-1H-indole-3-sulfonamide,6-chloro-N-[3,6-difluoro-5-(3-methoxypropyl)pyridin-2-yl]-1H-indole-3-sulfonamide,5-bromo-6-chloro-N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamide,6-chloro-N-(5-chloro-3,6-difluoropyridin-2-yl)-1H-indole-3-sulfonamide,6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-fluoro-1H-indole-3-sulfonamide,N-(4-cyano-2,5-difluorophenyl)-1H-benzo[g]indole-3-sulfonamide,7-bromo-6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-1H-indole-3-sulfonamide,6-chloro-N-[4-(cyanomethoxy)-2,5-difluorophenyl]-1H-indole-3-sulfonamide,N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide,6-chloro-N-(4-cyano-5-fluoro-2-methoxyphenyl)-1H-indole-3-sulfonamide,6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-1H-indole-3-sulfonamide,6-chloro-N-(5-ethyl-3,6-difluoropyridin-2-yl)-1H-indole-3-sulfonamide,6-chloro-N-{5-[(E)-2-ethoxyethenyl]-3,6-difluoropyridin-2-yl}-1H-indole-3-sulfonamide,6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-methoxy-1H-indole-3-sulfonamide,6-chloro-N-(4-chloro-2-fluorophenyl)-1H-indole-3-sulfonamide, ethyl 3-(6-{[(6-chloro- 1H-indo1-3-yl)sulfonyl]amino}-2,5-difluoropyridin-3-yl)propanoate,6-chloro-N-[2,5-difluoro-4-(trifluoromethyl)phenyl]-1H-indole-3-sulfonamide,6-bromo-N-{3,6-difluoro-5- [(1E)-3 -methoxyprop-1-en-1-yl]pyridin-2-yl}-1H-indole-3-sulfonamide, 6-chloro-N-[5-(cyanomethyl)-3 -fluoro-6-methoxypyridin-2-yl] -1-benzothiophene-3-sulfonamide, N-(2, 1,3-benzothiadiazol-4-yl)-6-bromo- 1H-indole-3- sulfonamide, 6-chloro-N-[4-(2,2-difluoroethoxy)-2,5-difluorophenyl] - 1H-indole-3-sulfonamide,ethyl (2E)-3 -(6-{[(6-chloro-1H-indo1-3-yl)sulfonyl]amino}-2,5-difluoropyridin-3-yl)prop-2-enoate,N-(5-chloro-3 -fluoropyridin-2-yl)-1H-benzo[g]indole-3-sulfonamide,N-(4-chloro-2,5-difluorophenyl)-8-(difluoromethyl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide,6-chloro-N-(4-chloro-2,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-7-methoxy-1H-indole-3-sulfonamide,6-chloro-N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-7-fluoro-1H-indole-3-sulfonamide,6-chloro-N-(2,5-difluoro-4-iodophenyl)-1H-indole-3- sulfonamide,N-(4-cyano-5-fluoro-2-methoxyphenyl)-1H-benzo [g] indole-3-sulfonamide,N- [4-(cyanomethoxy)-2,5-difluorophenyl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide,N-(4-cyano-2,5-difluorophenyl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide,6-chloro-N-(6-fluoro-2,1,3-benzothiadiazol-5-yl)-1H-indole-3-sulfonamide,6-chloro-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-1H-pyrrolo [2,3-b]pyridine-3-sulfonamide, N-(2, 1,3-benzoselenadiazol-4-yl)-6-chloro-1H-indole-3-sulfonamide,6-chloro-N-[2,5-difluoro-4-(trifluoromethyl)phenyl]-1H-pyrrolo [2,3-b]pyridine-3-sulfonamide,6-chloro-N-{3,6-difluoro-5-[(1E)-3-methoxyprop-1-en-1-yl]pyridin-2-yl}-1H-indole-3-sulfonamide, 6-chloro-N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide, 6-chloro-N-(2,5-difluoro-4-methylphenyl)- 1H-indole-3-sulfonamide, 6-chloro-N-[5-(2-ethoxyethyl)-3,6-difluoropyridin-2-yl]-1H-indole-3- sulfonamide,6-chloro-N-(5-chloro-3,6-difluoropyridin-2-yl)-7-methoxy-1H-indole-3-sulfonamide, N-(4-cyano-2-fluorophenyl)-6-(thiophen-2-yl)-1H-indole-3-sulfonamide,6-chloro-N-(4-ethynyl-2-fluorophenyl)-1H-indole-3-sulfonamide,6-chloro-N-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-1H-indole-3-sulfonamide,6-chloro-N-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-indole-3-sulfonamide,7-bromo-6-chloro-N-(4-cyano-2-fluorophenyl)-1H-indole-3- sulfonamide,6-bromo-N-(4-cyano-2-fluorophenyl)-1H-pyrrolo [2,3-b]pyridine-3-sulfonamide,6-chloro-N-(4-cyano-2,5-difluorophenyl)-1H-indole-3-sulfonamide,6-bromo-N-(2-fluoro-4-iodophenyl)- 1H-pyrrolo [2,3-b]pyridine-3-sulfonamide, N-(5-bromo-6-fluoro-3-methoxypyridin-2-yl)-6-chloro- 1H-indole-3-sulfonamide,6-chloro-N-(2-fluoro-4-iodophenyl)- 1H-indole-3- sulfonamide,6-chloro-N- [5-(cyanomethyl)-6-fluoro-3 -methoxypyridin-2-yl]-1H-indole-3- sulfonamide,6-bromo-7-chloro-N-(4-chloro-2,5-difluorophenyl)- 1H-indole-3-sulfonamide, 6-bromo-N-(6-fluoro-2,1,3-benzothiadiazol-5-yl)-1H-indole-3-sulfonamide, N-(4-bromo-2,5-difluorophenyl)-6-methoxy-1H-indole-3-sulfonamide, 6-bromo-N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide,6-chloro-N-(4-cyano-2-fluoro-5-methoxyphenyl)-1H-indole-3- sulfonamide,N-(5-chloro-3,6-difluoropyridin-2-yl)-1H-benzo [g]indole-3-sulfonamide,6-azido-N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamide, 6-chloro-N-[3,6-difluoro-5-(2-fluoroethoxy)pyridin-2-yl]-1H-indole-3- sulfonamide,6-chloro-N-(6-fluoro- 1-methyl-3 -oxo- 1,3 -dihydro-2-benzofuran-5-yl)-1H-indole-3 - sulfonamide,N-(4-chloro-2,5-difluorophenyl)-5H-[1,3]dioxolo[4,5-f]indole-7-sulfonamide,6-bromo-N-(5-chloro-3-fluoropyridin-2-yl)-1H-indole-3-sulfonamide,N-[4-(cyanomethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-1H-indole-3-sulfonamide,N-(2,1,3-benzothiadiazol-4-yl)-1H-benzo[g]indole-3-sulfonamide,6-bromo-N-(4-chloro-2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-(2,2-difluoroethoxy)-1H-indole-3-sulfonamide,6-bromo-N-(4-cyanophenyl)-1H-indole-3-sulfonamide,N-(2,1,3-benzothiadiazol-5-yl)-6-bromo-1H-indole-3-sulfonamide,N-(4-cyano-2-fluorophenyl)-6-(propan-2-yl)-1H-indole-3-sulfonamide,N-(4-cyano-2-fluorophenyl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide,N-(4-cyano-2,5-difluorophenyl)-6-methoxy-1H-indole-3-sulfonamide,N-(4-bromo-2,5-difluorophenyl)-6-methoxy-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,6-chloro-N-(5-ethenyl-3,6-difluoropyridin-2-yl)-1H-indole-3-sulfonamide,N-(4-bromo-2,5-difluorophenyl)-6-(methylsulfinyl)-1H-indole-3-sulfonamide,N-(4-bromo-2,5-difluorophenyl)-6-chloro-l-benzofuran-3-sulfonamide,N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(methylsulfinyl)-1H-indole-3-sulfonamide,6-chloro-N-(2,4,5-trifluorophenyl)-1H-indole-3-sulfonamide,N-(4-chloro-2,5-difluorophenyl)-8-hydroxy-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide,6-chloro-N-(2,5-difluoro-4-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-cyano-1H-indole-3-sulfonamide,6-chloro-N-[5-(cyanomethyl)-3-methoxypyridin-2-yl]-1H-indole-3-sulfonamide,N-[4-(2-cyanoethyl)-2,5-difluorophenyl]-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide,6-chloro-N-[4-(cyanomethyl)-2-fluorophenyl]-1H-indole-3-sulfonamide,N-(4-cyano-2-fluorophenyl)-1,6,7,8-tetrahydrocyclopenta[g]indole-3-sulfonamide,N-(2,1,3-benzothiadiazol-4-yl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide,N-(4-chloro-2,5-difluorophenyl)-6-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,N-(4-ethynyl-2-fluorophenyl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide,N-(4-bromo-2-fluorophenyl)-6-chloro-1H-indole-3-sulfonamide,6-bromo-N-(5-chloro-3-fluoropyridin-2-yl)-7-methyl-1H-indole-3-sulfonamide,6-chloro-N-[4-chloro-5-(difluoromethoxy)-2-fluorophenyl]-1H-indole-3-sulfonamide,N-(2,1,3-benzoxadiazol-5-yl)-6-chloro-1H-indole-3-sulfonamide,5-bromo-6-chloro-N-(4-cyano-2-fluorophenyl)-1H-indole-3-sulfonamide,6-(benzyloxy)-N-(4-cyano-2,5-difluorophenyl)-1H-indole-3-sulfonamide,N-(6-fluoro-2,1,3-benzothiadiazol-5-yl)-1H-benzo[g]indole-3-sulfonamide,N-(2,1,3-benzothiadiazol-4-yl)-6-chloro-1H-indole-3-sulfonamide,6-chloro-N-(3,6-difluoro-5-methylpyridin-2-yl)-1H-indole-3-sulfonamide,6-chloro-N-(4-cyanophenyl)-1H-indole-3-sulfonamide,6-chloro-N-(5-chloro-3-fluoropyridin-2-yl)-1H-indole-3-sulfonamide,N-(4-chloro-2,5-difluorophenyl)-6-methoxy-1H-indole-3-sulfonamide,N-(4-chloro-2,5-difluorophenyl)-6-(difluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,6-chloro-N-(3-chloro-4-cyanophenyl)-1H-indole-3-sulfonamide,7-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-6-fluoro-1H-indole-3-sulfonamide,6-chloro-N-[2-fluoro-4-(pentafluoro-lambda-6-sulfanyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,N-(4-cyanophenyl)-1H-benzo[g]indole-3-sulfonamide,N-(4-chloro-2-fluorophenyl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide,6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-5,7-difluoro-1H-indole-3-sulfonamide,N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-6-nitro-1H-indole-3-sulfonamide,6-chloro-N-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,6-chloro-N-[4-(cyanomethoxy)-2,5-difluorophenyl]-1-benzofuran-3-sulfonamide,N-(4-chloro-2,5-difluorophenyl)-6-cyano-1H-indole-3-sulfonamide,6-chloro-N-(2,2-difluoro-1,3-benzodioxo1-4-yl)-1H-indole-3-sulfonamide,6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-(methylsulfinyl)-1H-indole-3-sulfonamide,6-chloro-N-[3,6-difluoro-5-(propan-2-yl)pyridin-2-yl]-1H-indole-3-sulfonamide,6-chloro-N-(4-chloro-2,5-difluorophenyl)-1-benzofuran-3-sulfonamide,7-chloro-N-(4-chloro-2,5-difluorophenyl)-6-(methylsulfanyl)-1H-indole-3- sulfonamide, N-(2, 1,3-benzothiadiazol-4-yl)-6-chloro-1H-pyrrolo [2,3-b]pyridine-3-sulfonamide, 6-chloro-N-{5- [(difluoromethoxy)methyl]-3-fluoropyridin-2-yl}-1H-indole-3- sulfonamide, N-(1,3-benzodioxo1-4-yl)-6-chloro- 1H-indole-3-sulfonamide,6-(benzyloxy)-N-(4-cyano-2-fluorophenyl)- 1H-indole-3-sulfonamide,6-chloro-N-(3,6-difluoro-5-methylpyridin-2-yl)-7-fluoro-1H-indole-3-sulfonamide, N-(4-cyanophenyl)-6-cyclopropyl-1H-indole-3- sulfonamide,6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-5-fluoro-1H-indole-3-sulfonamide,7-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-6-methoxy-1H-indole-3-sulfonamide,6-chloro-N-(4-cyano-5-fluoro-2-methoxyphenyl)-1H-pyrrolo [2,3-b]pyridine-3-sulfonamide,6-chloro-N-(6-fluoro-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-1H-indole-3-sulfonamide,ethyl 2-(6-1[{(6-chloro-1H-indo1-3-yl)sulfonyl]amino}-2,5-difluoropyridin-3-yl)1016,N-(2, 1,3 -benzoxadiazol-4-yl)-6-chloro-1H-indole-3-sulfonamide,6-chloro-N-(4-cyanophenyl)-1H-pyrrolo [2,3 -b]pyridine-3-sulfonamide,6-chloro-N-(4-chloro-2-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-3-sulfonamide, N-(2, 1,3 -benzoxadiazol-4-yl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide,6-chloro-N-(4-chloro-5-fluoro-2-methoxyphenyl)-1H-indole-3-sulfonamide,6-chloro-N-(4-chloro-2,5-difluorophenyl)-1-benzothiophene-3-sulfonamide,6-chloro-N-[4-(cyanomethoxy)-2,5-difluorophenyl]-1-benzothiophene-3-sulfonamide,N-(2, 1,3-benzothiadiazol-4-yl)-6-bromo-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,6-bromo-N-(4-cyanophenyl)-1H-pyrrolo[2,3 -b]pyridine-3 - sulfonamide,6-chloro-N-(4-cyano-2,6-difluorophenyl)-1H-indole-3-sulfonamide,6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,N-(5-bromo-3-fluoropyridin-2-yl)-6-chloro- 1H-indole-3-sulfonamide,6-chloro-N-(4-cyano-2-fluorophenyl)-5-fluoro- 1H-indole-3-sulfonamide,N-(2,2-difluoro- 1,3 -benzodioxo1-4-yl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide,N-(5-chloro-3,6-difluoropyridin-2-yl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide, N-(4-bromo-2-fluorophenyl)-6-methyl-1H-indole-3- sulfonamide,6-bromo-N-(4-chloro-2,5-difluorophenyl)-4-fluoro-1H-indole-3-sulfonamide,N-(2, 1,3-benzothiadiazol-5-yl)-6-chloro-1H-indole-3-sulfonamide,N-(4-cyano-2-fluorophenyl)-6-methoxy-1 H-indole-3-sulfonamide,N-(4-chloro-2,5-difluorophenyl)-6-methoxy- 1H-pyrrolo [2,3-b]pyridine-3-sulfonamide,6-cyano-N-[4-(difluoromethoxy)-2,5-difluorophenyl]-1H-indole-3-sulfonamide,N-(4-chloro-2,5-difluorophenyl)-6-(methylsulfinyl)-1H-indole-3-sulfonamide,6-chloro-N-(6-fluoro-2,1,3-benzoxadiazol-5-yl)-1H-indole-3-sulfonamide,6-chloro-N-(3,5-difluoro-6-methoxypyridin-2-yl)-1H-indole-3-sulfonamide,N-(4-cyano-5-fluoro-2-methoxyphenyl)-6-methoxy-1H-indole-3-sulfonamide,N-[4-(difluoromethoxy)-2,5-difluorophenyl]-6-(difluoromethyl)-1H-pyrrolo[2,3 -b]pyridine-3-sulfonamide, N-(4-cyano-2-fluorophenyl)-6-(thiophen-3-yl)-1H-indole-3-sulfonamide,N-(4-azido-2-fluorophenyl)-6-chloro-1H-indole-3-sulfonamide,6-chloro-N-[2-fluoro-4-(trifluoromethoxy)phenyl]-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,6-chloro-N-(2-fluoro-4-iodophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,N-(5-bromo-6-chloropyridin-2-yl)-6-chloro-1H-indole-3-sulfonamide,N-(5-bromo-3-methoxypyridin-2-yl)-6-chloro-1H-indole-3- sulfonamide,6-chloro-N-[3-methoxy-5-(trifluoromethyl)pyridin-2-yl]-1H-indole-3-sulfonamide,6-chloro-N-(2,5-difluorophenyl)- 1H-indole-3-sulfonamide,6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-1-benzothiophene-3-sulfonamide,6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-(methylsulfonyl)-1H-indole-3-sulfonamide,6-chloro-N-(4-chloro-2,5-difluorophenyl)-5-fluoro-1H-indole-3-sulfonamide,N-(2-fluoro-4-iodophenyl)-5H-[1,3]dioxolo[4,5-f]indole-7-sulfonamide,N-[4-(cyanomethoxy)-2,5-difluorophenyl]-6-fluoro-1H-indole-3-sulfonamide,N-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methoxy-1H-indole-3-sulfonamide6-chloro-N-[2-fluoro-4-(pentafluoro-lambda-6-sulfanyl)phenyl]-1H-indole-3-sulfonamide,6-bromo-N-(2,4,5-trifluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,N-(2-fluoro-4-iodophenyl)-6-(methylsulfonyl)-1H-indole-3-sulfonamide,6-chloro-N-(7-fluoro-2,1,3-benzothiadiazol-4-yl)-1H-indole-3-sulfonamide,6-chloro-N-(3,6-difluoro-5-methylpyridin-2-yl)-7-(trifluoromethyl)-1H-indole-3-sulfonamide,6-chloro-N-(3,5-difluoro-6-methoxypyridin-2-yl)-7-fluoro-1H-indole-3-sulfonamide,6-chloro-N-[2-fluoro-4-(trifluoromethoxy)phenyl]-1H-indole-3-sulfonamide,6-chloro-N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-1-benzofuran-3-sulfonamide,6-chloro-N-(5-chloro-3-fluoro-6-methylpyridin-2-yl)-1H-indole-3-sulfonamide,N-(5-chloro-3-fluoro-6-methoxypyridin-2-yl)-6,7,8,9-tetrahydro-1H-benzo[g]indole-3-sulfonamide,6-bromo-N-(4-ethynylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,6-chloro-N-(2,2,6-trifluoro-1,3-benzodioxo1-5-yl)-1H-indole-3-sulfonamide,6-chloro-N-(4-chloro-2,5-difluorophenyl)-7-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-indole-3-sulfonamide,6-chloro-N-[5-chloro-3-fluoro-6-(fluoromethyl)pyridin-2-yl]-1H-indole-3-sulfonamide,6-chloro-N-(3-fluoro-5-methylpyridin-2-yl)-1H-indole-3-sulfonamide,6-chloro-N-(2,5-difluoro-4-methoxyphenyl)-1H-indole-3-sulfonamide,N-(4-chloro-2-fluorophenyl)-6-methyl-1H-indole-3-sulfonamide,N-(5-chloro-3,6-difluoropyridin-2-yl)-1,6,7,8-tetrahydrocyclopenta[g]indole-3-sulfonamide,6-chloro-N-(5-chloro-3,6-difluoropyridin-2-yl)-7-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-indole-3-sulfonamide,6-bromo-N-(2-chloro-3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,6-chloro-N-(5-chloro-3,6-difluoropyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,6-(methylsulfonyl)-N-(2,2,6-trifluoro-1,3-benzodioxo1-5-yl)-1H-indole-3-sulfonamide,6-chloro-N-[3,6-difluoro-5-(prop-1-en-2-yl)pyridin-2-yl]-1H-indole-3-sulfonamide,N-(5-chloro-3-fluoropyridin-2-yl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide,N-(2,1,3-benzothiadiazol-4-yl)-6-fluoro-1H-indole-3-sulfonamide,6-chloro-N-(5-chloro-2-fluorophenyl)-1H-indole-3-sulfonamide,N-(4-chloro-5-fluoro-2-methoxyphenyl)-1H-benzo[g]indole-3-sulfonamide,6-chloro-7-(difluoromethoxy)-N-(3,5-difluoro-6-methoxypyridin-2-yl)-1H-indole-3-sulfonamide,N-(4-chloro-2-fluorophenyl)-6-(methylsulfonyl)-1H-indole-3-sulfonamide,6-bromo-N-(2,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,N-(1,3-benzodioxo1-4-yl)-6-bromo-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,N-(2,1,3-benzothiadiazol-4-yl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide,N-(4-bromo-2-fluorophenyl)-6-methoxy-1H-indole-3-sulfonamide,N-(4-cyano-2-fluorophenyl)-6-(2,2,2-trifluoroethoxy)-1H-indole-3-sulfonamide,N-(2,4,5-trifluorophenyl)-1H-pyrrolo[3,2-h]quinoline-3-sulfonamide,N-(4-cyano-2-fluorophenyl)-6-(cyclopropylmethoxy)-1H-indole-3-sulfonamide,N-(4-ethynyl-2-fluorophenyl)-6-methoxy-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,6-chloro-N-(4-cyano-2-methoxyphenyl)-1H-indole-3-sulfonamide,N-(2,1,3-benzothiadiazol-5-yl)-6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,N-(4-ethynyl-2-fluorophenyl)-6-methoxy-1H-indole-3-sulfonamide,6-chloro-N-[3,6-difluoro-5-(2-methoxyethoxy)pyridin-2-yl]-1H-indole-3-sulfonamide,6-chloro-N-[4-(cyclopropylmethoxy)-2,5-difluorophenyl]-1H-indole-3-sulfonamide,6-chloro-N-[5-(difluoromethoxy)-3,6-difluoropyridin-2-yl]-1H-indole-3-sulfonamide,N-(2,1,3-benzothiadiazol-5-yl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide,6-bromo-N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamide,N-(4-cyano-2,5-difluorophenyl)-1,6,7,8-tetrahydrocyclopenta[g]indole-3-sulfonamide,7-bromo-6-chloro-N-[5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl]-1H-indole-3-sulfonamide,N-(4-cyano-2,5-difluorophenyl)-6-fluoro-1H-indole-3-sulfonamide,N-(4-cyanophenyl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide,N-(4-cyano-2,5-difluorophenyl)-6-methyl-1H-indole-3-sulfonamide,6-bromo-N-(2,2-difluoro-1,3-benzodioxo1-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,N-(2,1,3-benzoselenadiazol-5-yl)-6-chloro-1H-indole-3-sulfonamide,N-(4-cyanophenyl)-6-methyl-1H-indole-3-sulfonamide,6-chloro-N-(6-fluoro-2,1,3-benzothiadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,7-bromo-N-(4-cyano-2,5-difluorophenyl)-1H-indole-3-sulfonamide,6-chloro-N-(3,6-difluoro-5-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide,N-(2,5-difluoro-4-methylphenyl)-6-(methylsulfinyl)-1H-indole-3-sulfonamide,and6-fluoro-N-(6-fluoro-2,1,3-benzothiadiazol-5-yl)-1H-indole-3-sulfonamide.52. The method according to claim 31, wherein X1 is N or C(R7), X2 isNH, S or O, R4 and R5 are both hydrogen, R6 is selected from fluoro,chloro, bromo, cyano, azido, methyl, ethyl, isopropyl, fluoromethyl,cyclopropyl, methoxy, fluoromethoxy, methylsulfinyl, methylsulfonyl,thien-2-yl, thien-3-yl, and benzyloxy, R7 is selected from hydrogen,methoxy, fluoro, chloro, bromo, cyano, mono-, di-, and trifluoromethyl,methylsulfinyl, methylsulfonyl, and fluoro(C₁₋₂)alkoxy, X3 is N orC(R12), R8 is selected from fluoro and methoxy, R9 is hydrogen, R10 isselected from fluoro, chloro, bromo, azido, cyano, cyanomethyl,cyanoethyl, cyanomethoxy, cyclopropyl(C₁₋₂)alkyl,cyclopropyl(C₁₋₂)alkoxy, C₁₋₂alkoxycyclopropyl,C₁₋₂alkoxycarbonylcyclopropyl, unsubstituted or fluorinated C₁₋₃ alkyl,unsubstituted or fluorinated C₁₋₃ alkoxy, unsubstituted or fluorinatedC₂₋₃ alkenyl, unsubstituted or fluorinated C₂₋₃ alkynyl, unsubstitutedor fluorinated C₁₋₃ alkoxy(C₁₋₃)alkyl, unsubstituted or fluorinated C₁₋₃alkoxy(C₁₋₃)alkoxy, unsubstituted or fluorinated C₁₋₃alkoxy(C₂₋₃)alkenyl, and pentafluorosulfanyl, R11 is selected fromhydrogen, fluoro and methoxy, R12, if present, is hydrogen, andpharmaceutically acceptable salts, solvates, isotopes and co-crystalsthereof.
 53. The method according to claim 31, wherein the syndrome ordisorder is selected from the group consisting of multiple sclerosis(MS). a multiple sclerosis (MS) subform, neuromyelitis optica (Devic'sdisease), chronic relapsing inflammatory optic neuritis, acutedisseminated encephalomyelitis, acute haemorrhagic leucoencephalitis(AHL), periventricular leukomalacia, demyelination due to viralinfections, central pontine and extrapontine myelinolysis, demyelinationdue to traumatic brain tissue damage, demyelination in response tohypoxia, stroke or ischaemia or other cardiovascular diseases,demyelination due to exposure to carbon dioxide, cyanide, or other CNStoxins, Schilder's disease, Balo concentric sclerosis, perinatalencephalopathy, neurodegenerative diseases including amyotrophic lateralsclerosis (ALS). Alzheimer's disease (AD), multiple system atrophy,Parkinson's Disease, spinocerebellar ataxia (SCA) and HuntingtonDisease, psychiatric disorders such as schizophrenia and bipolardisorder and peripheral myelination diseases including leukodystrophies,peripheral neuropathies, Dejerine-Sottas syndrome andCharcot-Marie-Tooth disease.
 54. The method according to claim 31,wherein the syndrome or disorder is multiple sclerosis (MS).
 55. Themethod according to claim 33, wherein the syndrome or disorder ismultiple sclerosis (MS).
 56. The method according to claim 34, whereinthe syndrome or disorder is multiple sclerosis (MS).
 57. The methodaccording to claim 35, wherein the syndrome or disorder is multiplesclerosis (MS).
 58. The method according to claim 36, wherein thesyndrome or disorder is multiple sclerosis (MS).
 59. The methodaccording to claim 38, wherein the syndrome or disorder is multiplesclerosis (MS).
 60. The method according to claim 39, wherein thesyndrome or disorder is multiple sclerosis (MS).
 61. The methodaccording to claim 41, wherein the syndrome or disorder is multiplesclerosis (MS).
 62. The method according to claim 42, wherein thesyndrome or disorder is multiple sclerosis (MS).
 63. The methodaccording to claim 44, wherein the syndrome or disorder is multiplesclerosis (MS).
 64. The method according to claim 51, wherein thesyndrome or disorder is multiple sclerosis (MS).
 65. The methodaccording to claim 52, wherein the syndrome or disorder is multiplesclerosis (MS). END OF CLAIM LISTING